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  • Cell Line  (524)
  • Nature Publishing Group (NPG)  (524)
  • 1
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    A coding-independent function of gene and pseudogene mRNAs regulates tumour biology (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-06-26
    Description: The canonical role of messenger RNA (mRNA) is to deliver protein-coding information to sites of protein synthesis. However, given that microRNAs bind to RNAs, we hypothesized that RNAs could possess a regulatory role that relies on their ability to compete for microRNA binding, independently of their protein-coding function. As a model for the protein-coding-independent role of RNAs, we describe the functional relationship between the mRNAs produced by the PTEN tumour suppressor gene and its pseudogene PTENP1 and the critical consequences of this interaction. We find that PTENP1 is biologically active as it can regulate cellular levels of PTEN and exert a growth-suppressive role. We also show that the PTENP1 locus is selectively lost in human cancer. We extended our analysis to other cancer-related genes that possess pseudogenes, such as oncogenic KRAS. We also demonstrate that the transcripts of protein-coding genes such as PTEN are biologically active. These findings attribute a novel biological role to expressed pseudogenes, as they can regulate coding gene expression, and reveal a non-coding function for mRNAs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206313/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206313/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poliseno, Laura -- Salmena, Leonardo -- Zhang, Jiangwen -- Carver, Brett -- Haveman, William J -- Pandolfi, Pier Paolo -- R01 CA-82328-09/CA/NCI NIH HHS/ -- R01 CA102142/CA/NCI NIH HHS/ -- R01 CA102142-07/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2010 Jun 24;465(7301):1033-8. doi: 10.1038/nature09144.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20577206" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/genetics ; Binding, Competitive ; Cell Line ; Gene Expression Regulation, Neoplastic/*genetics ; Genes, Tumor Suppressor ; Humans ; MicroRNAs/*genetics ; Models, Genetic ; Neoplasms/*genetics ; PTEN Phosphohydrolase/*genetics ; Proto-Oncogene Proteins/genetics ; Pseudogenes/*genetics ; RNA, Messenger/*genetics ; ras Proteins/genetics
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  • 2
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    Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-01-19
    Description: Influenza A virus, being responsible for seasonal epidemics and reoccurring pandemics, represents a worldwide threat to public health. High mutation rates facilitate the generation of viral escape mutants, rendering vaccines and drugs directed against virus-encoded targets potentially ineffective. In contrast, targeting host cell determinants temporarily dispensable for the host but crucial for virus replication could prevent viral escape. Here we report the discovery of 287 human host cell genes influencing influenza A virus replication in a genome-wide RNA interference (RNAi) screen. Using an independent assay we confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the current pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. Notably, a subset of these common hits was also essential for replication of a highly pathogenic avian H5N1 strain. In-depth analyses of several factors provided insights into their infection stage relevance. Notably, SON DNA binding protein (SON) was found to be important for normal trafficking of influenza virions to late endosomes early in infection. We also show that a small molecule inhibitor of CDC-like kinase 1 (CLK1) reduces influenza virus replication by more than two orders of magnitude, an effect connected with impaired splicing of the viral M2 messenger RNA. Furthermore, influenza-virus-infected p27(-/-) (cyclin-dependent kinase inhibitor 1B; Cdkn1b) mice accumulated significantly lower viral titres in the lung, providing in vivo evidence for the importance of this gene. Thus, our results highlight the potency of genome-wide RNAi screening for the dissection of virus-host interactions and the identification of drug targets for a broad range of influenza viruses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Karlas, Alexander -- Machuy, Nikolaus -- Shin, Yujin -- Pleissner, Klaus-Peter -- Artarini, Anita -- Heuer, Dagmar -- Becker, Daniel -- Khalil, Hany -- Ogilvie, Lesley A -- Hess, Simone -- Maurer, Andre P -- Muller, Elke -- Wolff, Thorsten -- Rudel, Thomas -- Meyer, Thomas F -- England -- Nature. 2010 Feb 11;463(7282):818-22. doi: 10.1038/nature08760. Epub 2010 Jan 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Department, Max Planck Institute for Infection Biology, Chariteplatz 1, 10117 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20081832" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Factors/genetics/metabolism ; Cell Line ; Cells, Cultured ; Chick Embryo ; Cyclin-Dependent Kinase Inhibitor p27/deficiency/genetics/metabolism ; Epithelial Cells/virology ; Genome, Human/genetics ; *Host-Pathogen Interactions/genetics/physiology ; Humans ; Influenza A Virus, H1N1 Subtype/classification/*growth & development ; Influenza, Human/*genetics/*virology ; Lung/cytology ; Mice ; Mice, Inbred C57BL ; Protein-Serine-Threonine Kinases/genetics ; Protein-Tyrosine Kinases/genetics ; *RNA Interference ; Virus Replication/*physiology
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  • 3
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    Enzyme-inhibitor-like tuning of Ca(2+) channel connectivity with calmodulin (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-02-09
    Description: Ca(2+) channels and calmodulin (CaM) are two prominent signalling hubs that synergistically affect functions as diverse as cardiac excitability, synaptic plasticity and gene transcription. It is therefore fitting that these hubs are in some sense coordinated, as the opening of Ca(V)1-2 Ca(2+) channels are regulated by a single CaM constitutively complexed with channels. The Ca(2+)-free form of CaM (apoCaM) is already pre-associated with the isoleucine-glutamine (IQ) domain on the channel carboxy terminus, and subsequent Ca(2+) binding to this 'resident' CaM drives conformational changes that then trigger regulation of channel opening. Another potential avenue for channel-CaM coordination could arise from the absence of Ca(2+) regulation in channels lacking a pre-associated CaM. Natural fluctuations in CaM concentrations might then influence the fraction of regulable channels and, thereby, the overall strength of Ca(2+) feedback. However, the prevailing view has been that the ultrastrong affinity of channels for apoCaM ensures their saturation with CaM, yielding a significant form of concentration independence between Ca(2+) channels and CaM. Here we show that significant exceptions to this autonomy exist, by combining electrophysiology (to characterize channel regulation) with optical fluorescence resonance energy transfer (FRET) sensor determination of free-apoCaM concentration in live cells. This approach translates quantitative CaM biochemistry from the traditional test-tube context into the realm of functioning holochannels within intact cells. From this perspective, we find that long splice forms of Ca(V)1.3 and Ca(V)1.4 channels include a distal carboxy tail that resembles an enzyme competitive inhibitor that retunes channel affinity for apoCaM such that natural CaM variations affect the strength of Ca(2+) feedback modulation. Given the ubiquity of these channels, the connection between ambient CaM levels and Ca(2+) entry through channels is broadly significant for Ca(2+) homeostasis. Strategies such as ours promise key advances for the in situ analysis of signalling molecules resistant to in vitro reconstitution, such as Ca(2+) channels.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553577/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553577/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Xiaodong -- Yang, Philemon S -- Yang, Wanjun -- Yue, David T -- P30 DC005211/DC/NIDCD NIH HHS/ -- R01 DC000276/DC/NIDCD NIH HHS/ -- England -- Nature. 2010 Feb 18;463(7283):968-72. doi: 10.1038/nature08766. Epub 2010 Feb 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Calcium Signals Laboratory, Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20139964" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Animals ; Apoproteins/analysis/metabolism ; Binding, Competitive/drug effects ; Calcium/analysis/metabolism/pharmacology ; Calcium Channel Blockers/*chemistry/*metabolism ; Calcium Channels/*chemistry/genetics/*metabolism ; Calmodulin/analysis/*metabolism ; Cell Line ; Cell Survival ; Electrophysiology ; *Feedback, Physiological ; Fluorescence Resonance Energy Transfer ; Humans ; Protein Structure, Tertiary ; Rats ; Recombinant Fusion Proteins/chemistry/genetics/metabolism
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  • 4
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    Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect (2010)
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    Publication Date: 2010-04-23
    Description: The worldwide prevalence of chronic hepatitis C virus (HCV) infection is estimated to be approaching 200 million people. Current therapy relies upon a combination of pegylated interferon-alpha and ribavirin, a poorly tolerated regimen typically associated with less than 50% sustained virological response rate in those infected with genotype 1 virus. The development of direct-acting antiviral agents to treat HCV has focused predominantly on inhibitors of the viral enzymes NS3 protease and the RNA-dependent RNA polymerase NS5B. Here we describe the profile of BMS-790052, a small molecule inhibitor of the HCV NS5A protein that exhibits picomolar half-maximum effective concentrations (EC(50)) towards replicons expressing a broad range of HCV genotypes and the JFH-1 genotype 2a infectious virus in cell culture. In a phase I clinical trial in patients chronically infected with HCV, administration of a single 100-mg dose of BMS-790052 was associated with a 3.3 log(10) reduction in mean viral load measured 24 h post-dose that was sustained for an additional 120 h in two patients infected with genotype 1b virus. Genotypic analysis of samples taken at baseline, 24 and 144 h post-dose revealed that the major HCV variants observed had substitutions at amino-acid positions identified using the in vitro replicon system. These results provide the first clinical validation of an inhibitor of HCV NS5A, a protein with no known enzymatic function, as an approach to the suppression of virus replication that offers potential as part of a therapeutic regimen based on combinations of HCV inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Min -- Nettles, Richard E -- Belema, Makonen -- Snyder, Lawrence B -- Nguyen, Van N -- Fridell, Robert A -- Serrano-Wu, Michael H -- Langley, David R -- Sun, Jin-Hua -- O'Boyle, Donald R 2nd -- Lemm, Julie A -- Wang, Chunfu -- Knipe, Jay O -- Chien, Caly -- Colonno, Richard J -- Grasela, Dennis M -- Meanwell, Nicholas A -- Hamann, Lawrence G -- England -- Nature. 2010 May 6;465(7294):96-100. doi: 10.1038/nature08960. Epub 2010 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Virology, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20410884" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Animals ; Antiviral Agents/blood/chemistry/*pharmacology/therapeutic use ; Cell Line ; Cercopithecus aethiops ; Drug Resistance, Viral ; Female ; Genotype ; HeLa Cells ; Hepacivirus/*drug effects ; Hepatitis C/drug therapy/virology ; Humans ; Imidazoles/blood/chemistry/*pharmacology ; Inhibitory Concentration 50 ; Male ; Middle Aged ; Time Factors ; Vero Cells ; Viral Load/drug effects ; Viral Nonstructural Proteins/*antagonists & inhibitors ; Young Adult
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  • 5
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    RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF (2010)
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    Publication Date: 2010-02-25
    Description: Tumours with mutant BRAF are dependent on the RAF-MEK-ERK signalling pathway for their growth. We found that ATP-competitive RAF inhibitors inhibit ERK signalling in cells with mutant BRAF, but unexpectedly enhance signalling in cells with wild-type BRAF. Here we demonstrate the mechanistic basis for these findings. We used chemical genetic methods to show that drug-mediated transactivation of RAF dimers is responsible for paradoxical activation of the enzyme by inhibitors. Induction of ERK signalling requires direct binding of the drug to the ATP-binding site of one kinase of the dimer and is dependent on RAS activity. Drug binding to one member of RAF homodimers (CRAF-CRAF) or heterodimers (CRAF-BRAF) inhibits one protomer, but results in transactivation of the drug-free protomer. In BRAF(V600E) tumours, RAS is not activated, thus transactivation is minimal and ERK signalling is inhibited in cells exposed to RAF inhibitors. These results indicate that RAF inhibitors will be effective in tumours in which BRAF is mutated. Furthermore, because RAF inhibitors do not inhibit ERK signalling in other cells, the model predicts that they would have a higher therapeutic index and greater antitumour activity than mitogen-activated protein kinase (MEK) inhibitors, but could also cause toxicity due to MEK/ERK activation. These predictions have been borne out in a recent clinical trial of the RAF inhibitor PLX4032 (refs 4, 5). The model indicates that promotion of RAF dimerization by elevation of wild-type RAF expression or RAS activity could lead to drug resistance in mutant BRAF tumours. In agreement with this prediction, RAF inhibitors do not inhibit ERK signalling in cells that coexpress BRAF(V600E) and mutant RAS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178447/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178447/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poulikakos, Poulikos I -- Zhang, Chao -- Bollag, Gideon -- Shokat, Kevan M -- Rosen, Neal -- 1P01CA129243-02/CA/NCI NIH HHS/ -- 2R01EB001987/EB/NIBIB NIH HHS/ -- P01 CA129243-010002/CA/NCI NIH HHS/ -- R01 EB001987/EB/NIBIB NIH HHS/ -- U01 CA091178/CA/NCI NIH HHS/ -- U01 CA091178-01/CA/NCI NIH HHS/ -- England -- Nature. 2010 Mar 18;464(7287):427-30. doi: 10.1038/nature08902.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Molecular Pharmacology and Chemistry and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20179705" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Catalytic Domain ; Cell Line ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Indoles/pharmacology ; MAP Kinase Signaling System/*drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Models, Biological ; Neoplasms/drug therapy/enzymology/genetics/metabolism ; Phosphorylation ; Protein Binding ; Protein Kinase Inhibitors/metabolism/*pharmacology/therapeutic use ; Protein Multimerization ; Proto-Oncogene Proteins B-raf/antagonists & ; inhibitors/chemistry/genetics/*metabolism ; Sulfonamides/pharmacology ; Transcriptional Activation/*drug effects ; raf Kinases/*antagonists & inhibitors/chemistry/genetics/*metabolism ; ras Proteins/genetics/metabolism
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  • 6
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    Unify guidelines for reviewing embryonic stem-cell research (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-07-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johnston, Josephine -- England -- Nature. 2010 Jul 8;466(7303):179. doi: 10.1038/466179a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20613819" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Consent Forms/legislation & jurisprudence ; Embryo Research/ethics/*legislation & jurisprudence ; *Embryonic Stem Cells/cytology ; Guidelines as Topic/*standards ; Humans ; Tissue and Organ Procurement/legislation & jurisprudence
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  • 7
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    Direct conversion of fibroblasts to functional neurons by defined factors (2010)
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    Publication Date: 2010-01-29
    Description: Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors, Ascl1, Brn2 (also called Pou3f2) and Myt1l, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons in vitro. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829121/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829121/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vierbuchen, Thomas -- Ostermeier, Austin -- Pang, Zhiping P -- Kokubu, Yuko -- Sudhof, Thomas C -- Wernig, Marius -- 1018438-142-PABCA/PHS HHS/ -- 5T32NS007280/NS/NINDS NIH HHS/ -- T32 CA009302/CA/NCI NIH HHS/ -- U01 HL100397/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Feb 25;463(7284):1035-41. doi: 10.1038/nature08797. Epub 2010 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Stem Cell Biology and Regenerative Medicine, Department of Pathology, Stanford University School of Medicine, 1050 Arastradero Road, Palo Alto, California 94304, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20107439" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism ; Biomarkers/analysis ; Cell Line ; *Cell Lineage ; *Cell Transdifferentiation ; Cells, Cultured ; Embryo, Mammalian/cytology ; Fibroblasts/*cytology ; Mice ; Nerve Tissue Proteins/genetics/metabolism ; Neurons/*cytology/metabolism/*physiology ; POU Domain Factors/genetics/metabolism ; Regenerative Medicine ; Synapses/metabolism ; Tail/cytology ; Time Factors ; Transcription Factors/genetics/metabolism
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    A population-specific HTR2B stop codon predisposes to severe impulsivity (2010)
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    Publication Date: 2010-12-24
    Description: Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency 〉 1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183507/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183507/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bevilacqua, Laura -- Doly, Stephane -- Kaprio, Jaakko -- Yuan, Qiaoping -- Tikkanen, Roope -- Paunio, Tiina -- Zhou, Zhifeng -- Wedenoja, Juho -- Maroteaux, Luc -- Diaz, Silvina -- Belmer, Arnaud -- Hodgkinson, Colin A -- Dell'osso, Liliana -- Suvisaari, Jaana -- Coccaro, Emil -- Rose, Richard J -- Peltonen, Leena -- Virkkunen, Matti -- Goldman, David -- AA-09203/AA/NIAAA NIH HHS/ -- AA-12502/AA/NIAAA NIH HHS/ -- Z01 AA000301-09/Intramural NIH HHS/ -- Z01 AA000301-10/Intramural NIH HHS/ -- Z99 AA999999/Intramural NIH HHS/ -- England -- Nature. 2010 Dec 23;468(7327):1061-6. doi: 10.1038/nature09629.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, Maryland 20852, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21179162" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/metabolism ; Case-Control Studies ; Cell Line ; Female ; Finland ; Founder Effect ; Gene Expression Regulation ; Gene Knockout Techniques ; Genotype ; Humans ; Impulsive Behavior/*genetics ; Male ; Mental Disorders/genetics ; Mice ; Mice, 129 Strain ; Mice, Knockout ; Pedigree ; Polymorphism, Single Nucleotide/genetics ; Receptor, Serotonin, 5-HT2B/*genetics/*metabolism ; Testosterone/blood/cerebrospinal fluid
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    Can controversies be put to REST? (2010)
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    Publication Date: 2010-09-03
    Description: The contribution of REST to embryonic stem (ES) cell pluripotency has been uncertain. Two years ago, Singh et al. claimed that Rest(+/-) and REST knock-down ES cells expressed reduced levels of pluripotency markers, in contrast to a prior and subsequent reports. To understand the basis of this difference, we analysed the YHC334 (YHC) and RRC160 (RRC) gene-trap ES cell lines used by Singh et al., obtained directly from BayGenomics. Both REST mutant lines generated REST-betaGeo fusion proteins, but expressed pluripotency genes at levels similar to appropriately matched parental wild ES cells, consistent with expression being REST-independent.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jorgensen, Helle F -- Fisher, Amanda G -- MC_U120027516/Medical Research Council/United Kingdom -- England -- Nature. 2010 Sep 2;467(7311):E3-4; discussion E5. doi: 10.1038/nature09305.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK. amanda.fisher@csc.mrc.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20811409" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Embryonic Stem Cells/*cytology ; Mice ; Mutagenesis, Insertional ; Pluripotent Stem Cells/*cytology ; Recombinant Fusion Proteins/genetics ; Repressor Proteins/*genetics
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    Reprogramming towards pluripotency requires AID-dependent DNA demethylation (2009)
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    Publication Date: 2009-12-23
    Description: Reprogramming of somatic cell nuclei to yield induced pluripotent stem (iPS) cells makes possible derivation of patient-specific stem cells for regenerative medicine. However, iPS cell generation is asynchronous and slow (2-3 weeks), the frequency is low (〈0.1%), and DNA demethylation constitutes a bottleneck. To determine regulatory mechanisms involved in reprogramming, we generated interspecies heterokaryons (fused mouse embryonic stem (ES) cells and human fibroblasts) that induce reprogramming synchronously, frequently and fast. Here we show that reprogramming towards pluripotency in single heterokaryons is initiated without cell division or DNA replication, rapidly (1 day) and efficiently (70%). Short interfering RNA (siRNA)-mediated knockdown showed that activation-induced cytidine deaminase (AID, also known as AICDA) is required for promoter demethylation and induction of OCT4 (also known as POU5F1) and NANOG gene expression. AID protein bound silent methylated OCT4 and NANOG promoters in fibroblasts, but not active demethylated promoters in ES cells. These data provide new evidence that mammalian AID is required for active DNA demethylation and initiation of nuclear reprogramming towards pluripotency in human somatic cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906123/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906123/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bhutani, Nidhi -- Brady, Jennifer J -- Damian, Mara -- Sacco, Alessandra -- Corbel, Stephane Y -- Blau, Helen M -- AG009521/AG/NIA NIH HHS/ -- AG024987/AG/NIA NIH HHS/ -- AI007328/AI/NIAID NIH HHS/ -- R01 AG009521/AG/NIA NIH HHS/ -- R01 AG009521-25/AG/NIA NIH HHS/ -- R01 AG024987/AG/NIA NIH HHS/ -- R01 AG024987-05/AG/NIA NIH HHS/ -- T32 AI007328/AI/NIAID NIH HHS/ -- U01 HL100397/HL/NHLBI NIH HHS/ -- England -- Nature. 2010 Feb 25;463(7284):1042-7. doi: 10.1038/nature08752.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Baxter Laboratory for Stem Cell Biology, Institute for Stem Cell Biology and Regenerative Medicine, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305-5175, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20027182" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Division ; Cell Fusion ; Cell Line ; Cells, Cultured ; Cellular Reprogramming/genetics/*physiology ; Chromatin Immunoprecipitation ; Cytidine Deaminase/deficiency/genetics/*metabolism ; DNA/chemistry/genetics/metabolism ; *DNA Methylation ; DNA Replication ; Embryonic Stem Cells/cytology/metabolism ; Fibroblasts/cytology/metabolism ; Gene Expression Regulation ; Gene Knockdown Techniques ; Homeodomain Proteins/genetics ; Humans ; Induced Pluripotent Stem Cells/*cytology/enzymology/*metabolism ; Lung/cytology/embryology ; Mice ; Models, Biological ; Octamer Transcription Factor-3/genetics ; Promoter Regions, Genetic/genetics ; Time Factors
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands (2010)
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    Publication Date: 2010-10-12
    Description: Reciprocity of inflammation, oxidative stress and neovascularization is emerging as an important mechanism underlying numerous processes from tissue healing and remodelling to cancer progression. Whereas the mechanism of hypoxia-driven angiogenesis is well understood, the link between inflammation-induced oxidation and de novo blood vessel growth remains obscure. Here we show that the end products of lipid oxidation, omega-(2-carboxyethyl)pyrrole (CEP) and other related pyrroles, are generated during inflammation and wound healing and accumulate at high levels in ageing tissues in mice and in highly vascularized tumours in both murine and human melanoma. The molecular patterns of carboxyalkylpyrroles are recognized by Toll-like receptor 2 (TLR2), but not TLR4 or scavenger receptors on endothelial cells, leading to an angiogenic response that is independent of vascular endothelial growth factor. CEP promoted angiogenesis in hindlimb ischaemia and wound healing models through MyD88-dependent TLR2 signalling. Neutralization of endogenous carboxyalkylpyrroles impaired wound healing and tissue revascularization and diminished tumour angiogenesis. Both TLR2 and MyD88 are required for CEP-induced stimulation of Rac1 and endothelial migration. Taken together, these findings establish a new function of TLR2 as a sensor of oxidation-associated molecular patterns, providing a key link connecting inflammation, oxidative stress, innate immunity and angiogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990914/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990914/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉West, Xiaoxia Z -- Malinin, Nikolay L -- Merkulova, Alona A -- Tischenko, Mira -- Kerr, Bethany A -- Borden, Ernest C -- Podrez, Eugene A -- Salomon, Robert G -- Byzova, Tatiana V -- CA126847/CA/NCI NIH HHS/ -- GM021249/GM/NIGMS NIH HHS/ -- HL071625/HL/NHLBI NIH HHS/ -- HL073311/HL/NHLBI NIH HHS/ -- HL077213/HL/NHLBI NIH HHS/ -- R01 HL071625/HL/NHLBI NIH HHS/ -- R01 HL071625-07/HL/NHLBI NIH HHS/ -- R01 HL071625-08/HL/NHLBI NIH HHS/ -- R01 HL077213/HL/NHLBI NIH HHS/ -- England -- Nature. 2010 Oct 21;467(7318):972-6. doi: 10.1038/nature09421. Epub 2010 Oct 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Cardiology, J. J. Jacobs Center for Thrombosis and Vascular Biology, NB50, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20927103" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/metabolism ; Animals ; Antigens, CD31/metabolism ; Aorta/cytology/drug effects ; Cell Line ; Cell Movement ; Endothelial Cells/metabolism ; Hindlimb/metabolism ; Humans ; Immunity, Innate/immunology ; Inflammation/metabolism ; Ischemia/metabolism ; Ligands ; Melanoma/blood supply/metabolism ; Mice ; Mice, Inbred C57BL ; Myeloid Differentiation Factor 88/metabolism ; Neovascularization, Pathologic/*metabolism ; *Neovascularization, Physiologic/drug effects ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Propionates ; Pyrroles/chemistry/*metabolism/pharmacology ; Receptors, Scavenger/metabolism ; Signal Transduction/drug effects ; Toll-Like Receptor 2/agonists/*metabolism ; Toll-Like Receptor 4/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Wound Healing/drug effects/physiology ; rac1 GTP-Binding Protein/metabolism
    Print ISSN: 0028-0836
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    Functional genomic screen for modulators of ciliogenesis and cilium length (2010)
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    Publication Date: 2010-04-16
    Description: Primary cilia are evolutionarily conserved cellular organelles that organize diverse signalling pathways. Defects in the formation or function of primary cilia are associated with a spectrum of human diseases and developmental abnormalities. Genetic screens in model organisms have discovered core machineries of cilium assembly and maintenance. However, regulatory molecules that coordinate the biogenesis of primary cilia with other cellular processes, including cytoskeletal organization, vesicle trafficking and cell-cell adhesion, remain to be identified. Here we report the results of a functional genomic screen using RNA interference (RNAi) to identify human genes involved in ciliogenesis control. The screen identified 36 positive and 13 negative ciliogenesis modulators, which include molecules involved in actin dynamics and vesicle trafficking. Further investigation demonstrated that blocking actin assembly facilitates ciliogenesis by stabilizing the pericentrosomal preciliary compartment (PPC), a previously uncharacterized compact vesiculotubular structure storing transmembrane proteins destined for cilia during the early phase of ciliogenesis. The PPC was labelled by recycling endosome markers. Moreover, knockdown of modulators that are involved in the endocytic recycling pathway affected the formation of the PPC as well as ciliogenesis. Our results uncover a critical regulatory step that couples actin dynamics and endocytic recycling with ciliogenesis, and also provides potential target molecules for future study.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929961/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2929961/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Joon -- Lee, Ji Eun -- Heynen-Genel, Susanne -- Suyama, Eigo -- Ono, Keiichiro -- Lee, Kiyoung -- Ideker, Trey -- Aza-Blanc, Pedro -- Gleeson, Joseph G -- GM070743/GM/NIGMS NIH HHS/ -- P30 CA023100/CA/NCI NIH HHS/ -- P30 CA23100/CA/NCI NIH HHS/ -- P30 NS047101/NS/NINDS NIH HHS/ -- P30 NS057096/NS/NINDS NIH HHS/ -- R01 GM070743/GM/NIGMS NIH HHS/ -- R01 NS052455/NS/NINDS NIH HHS/ -- R01 NS052455-05/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Apr 15;464(7291):1048-51. doi: 10.1038/nature08895.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurosciences, Institute for Genomic Medicine, Howard Hughes Medical Institute, University of California San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20393563" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/metabolism ; Cell Line ; Cilia/drug effects/*genetics/pathology/*physiology ; Cytochalasin D/pharmacology ; Endocytosis ; Humans ; RNA Interference ; Tumor Suppressor Proteins/genetics/metabolism
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    Comprehensive methylome map of lineage commitment from haematopoietic progenitors (2010)
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    Publication Date: 2010-08-20
    Description: Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956609/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956609/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ji, Hong -- Ehrlich, Lauren I R -- Seita, Jun -- Murakami, Peter -- Doi, Akiko -- Lindau, Paul -- Lee, Hwajin -- Aryee, Martin J -- Irizarry, Rafael A -- Kim, Kitai -- Rossi, Derrick J -- Inlay, Matthew A -- Serwold, Thomas -- Karsunky, Holger -- Ho, Lena -- Daley, George Q -- Weissman, Irving L -- Feinberg, Andrew P -- CA09151/CA/NCI NIH HHS/ -- F32 AI058521/AI/NIAID NIH HHS/ -- F32 AI058521-02/AI/NIAID NIH HHS/ -- F32AI058521/AI/NIAID NIH HHS/ -- P50 HG003233/HG/NHGRI NIH HHS/ -- P50 HG003233-07/HG/NHGRI NIH HHS/ -- P50 HG003233-08/HG/NHGRI NIH HHS/ -- P50HG003233/HG/NHGRI NIH HHS/ -- R00 AG029760/AG/NIA NIH HHS/ -- R00 AG029760-04/AG/NIA NIH HHS/ -- R00AGO29760/PHS HHS/ -- R01 AI047457/AI/NIAID NIH HHS/ -- R01 AI047457-04/AI/NIAID NIH HHS/ -- R01 AI047457-05/AI/NIAID NIH HHS/ -- R01 AI047458/AI/NIAID NIH HHS/ -- R01 CA086065/CA/NCI NIH HHS/ -- R01 GM083084/GM/NIGMS NIH HHS/ -- R01 GM083084-04/GM/NIGMS NIH HHS/ -- R01AI047457/AI/NIAID NIH HHS/ -- R01AI047458/AI/NIAID NIH HHS/ -- R37 CA054358/CA/NCI NIH HHS/ -- R37 CA054358-18/CA/NCI NIH HHS/ -- R37 CA054358-19/CA/NCI NIH HHS/ -- R37CA053458/CA/NCI NIH HHS/ -- England -- Nature. 2010 Sep 16;467(7313):338-42. doi: 10.1038/nature09367. Epub 2010 Aug 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Epigenetics and Department of Medicine, Johns Hopkins University School of Medicine, 570 Rangos, 725 N. Wolfe St., Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20720541" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; *Cell Lineage/genetics ; CpG Islands/genetics ; *DNA Methylation/genetics ; Epigenesis, Genetic ; Gene Expression Profiling ; Genome/genetics ; *Hematopoiesis/genetics ; Hematopoietic Stem Cells/*cytology/*metabolism ; Lymphocytes/cytology/metabolism ; Metabolome ; Metabolomics ; Mice ; Myeloid Cells/cytology/metabolism ; Pluripotent Stem Cells/cytology/metabolism
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    A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity (2010)
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    Publication Date: 2010-10-19
    Description: The derivation of human ES cells (hESCs) from human blastocysts represents one of the milestones in stem cell biology. The full potential of hESCs in research and clinical applications requires a detailed understanding of the genetic network that governs the unique properties of hESCs. Here, we report a genome-wide RNA interference screen to identify genes which regulate self-renewal and pluripotency properties in hESCs. Interestingly, functionally distinct complexes involved in transcriptional regulation and chromatin remodelling are among the factors identified in the screen. To understand the roles of these potential regulators of hESCs, we studied transcription factor PRDM14 to gain new insights into its functional roles in the regulation of pluripotency. We showed that PRDM14 regulates directly the expression of key pluripotency gene POU5F1 through its proximal enhancer. Genome-wide location profiling experiments revealed that PRDM14 colocalized extensively with other key transcription factors such as OCT4, NANOG and SOX2, indicating that PRDM14 is integrated into the core transcriptional regulatory network. More importantly, in a gain-of-function assay, we showed that PRDM14 is able to enhance the efficiency of reprogramming of human fibroblasts in conjunction with OCT4, SOX2 and KLF4. Altogether, our study uncovers a wealth of novel hESC regulators wherein PRDM14 exemplifies a key transcription factor required for the maintenance of hESC identity and the reacquisition of pluripotency in human somatic cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chia, Na-Yu -- Chan, Yun-Shen -- Feng, Bo -- Lu, Xinyi -- Orlov, Yuriy L -- Moreau, Dimitri -- Kumar, Pankaj -- Yang, Lin -- Jiang, Jianming -- Lau, Mei-Sheng -- Huss, Mikael -- Soh, Boon-Seng -- Kraus, Petra -- Li, Pin -- Lufkin, Thomas -- Lim, Bing -- Clarke, Neil D -- Bard, Frederic -- Ng, Huck-Hui -- England -- Nature. 2010 Nov 11;468(7321):316-20. doi: 10.1038/nature09531. Epub 2010 Oct 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Regulation Laboratory, Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20953172" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Line ; Cellular Reprogramming/genetics ; DNA-Binding Proteins/genetics/metabolism ; Embryonic Stem Cells/*cytology/*metabolism ; Enhancer Elements, Genetic/genetics ; Fibroblasts/cytology/metabolism ; Gene Expression Regulation/genetics ; Genome, Human/*genetics ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism ; Mice ; Octamer Transcription Factor-3/genetics/metabolism ; *RNA Interference ; Repressor Proteins/genetics/*metabolism ; SOXB1 Transcription Factors/metabolism
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    Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1 (2010)
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    Publication Date: 2010-04-02
    Description: Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca(2+) influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca(2+) concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1alpha expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Iwabu, Masato -- Yamauchi, Toshimasa -- Okada-Iwabu, Miki -- Sato, Koji -- Nakagawa, Tatsuro -- Funata, Masaaki -- Yamaguchi, Mamiko -- Namiki, Shigeyuki -- Nakayama, Ryo -- Tabata, Mitsuhisa -- Ogata, Hitomi -- Kubota, Naoto -- Takamoto, Iseki -- Hayashi, Yukiko K -- Yamauchi, Naoko -- Waki, Hironori -- Fukayama, Masashi -- Nishino, Ichizo -- Tokuyama, Kumpei -- Ueki, Kohjiro -- Oike, Yuichi -- Ishii, Satoshi -- Hirose, Kenzo -- Shimizu, Takao -- Touhara, Kazushige -- Kadowaki, Takashi -- England -- Nature. 2010 Apr 29;464(7293):1313-9. doi: 10.1038/nature08991. Epub 2010 Mar 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20357764" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/*metabolism ; Adiponectin/*metabolism ; Animals ; Calcium/*metabolism ; Calcium Signaling ; Calcium-Calmodulin-Dependent Protein Kinase Kinase/metabolism ; Cell Line ; Glucose/metabolism ; Homeostasis ; Insulin/metabolism ; Insulin Resistance ; Mice ; Mitochondria/*metabolism ; Muscle Cells/cytology/metabolism ; Muscle, Skeletal/cytology/metabolism ; Oocytes/metabolism ; Oxidative Stress ; Physical Conditioning, Animal ; Receptors, Adiponectin/deficiency/*metabolism ; Sirtuin 1/*metabolism ; Trans-Activators/*metabolism ; Transcription Factors ; Xenopus laevis
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    PHF8 mediates histone H4 lysine 20 demethylation events involved in cell cycle progression (2010)
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    Publication Date: 2010-07-14
    Description: While reversible histone modifications are linked to an ever-expanding range of biological functions, the demethylases for histone H4 lysine 20 and their potential regulatory roles remain unknown. Here we report that the PHD and Jumonji C (JmjC) domain-containing protein, PHF8, while using multiple substrates, including H3K9me1/2 and H3K27me2, also functions as an H4K20me1 demethylase. PHF8 is recruited to promoters by its PHD domain based on interaction with H3K4me2/3 and controls G1-S transition in conjunction with E2F1, HCF-1 (also known as HCFC1) and SET1A (also known as SETD1A), at least in part, by removing the repressive H4K20me1 mark from a subset of E2F1-regulated gene promoters. Phosphorylation-dependent PHF8 dismissal from chromatin in prophase is apparently required for the accumulation of H4K20me1 during early mitosis, which might represent a component of the condensin II loading process. Accordingly, the HEAT repeat clusters in two non-structural maintenance of chromosomes (SMC) condensin II subunits, N-CAPD3 and N-CAPG2 (also known as NCAPD3 and NCAPG2, respectively), are capable of recognizing H4K20me1, and ChIP-Seq analysis demonstrates a significant overlap of condensin II and H4K20me1 sites in mitotic HeLa cells. Thus, the identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059551/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059551/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Wen -- Tanasa, Bogdan -- Tyurina, Oksana V -- Zhou, Tian Yuan -- Gassmann, Reto -- Liu, Wei Ting -- Ohgi, Kenneth A -- Benner, Chris -- Garcia-Bassets, Ivan -- Aggarwal, Aneel K -- Desai, Arshad -- Dorrestein, Pieter C -- Glass, Christopher K -- Rosenfeld, Michael G -- R01 CA097134/CA/NCI NIH HHS/ -- R01 CA097134-09/CA/NCI NIH HHS/ -- R01 DK018477/DK/NIDDK NIH HHS/ -- R01 DK018477-35/DK/NIDDK NIH HHS/ -- R01 DK039949/DK/NIDDK NIH HHS/ -- R01 DK039949-18/DK/NIDDK NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R01 NS034934-21/NS/NINDS NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Jul 22;466(7305):508-12. doi: 10.1038/nature09272. Epub 2010 Jul 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, School of Medicine, University of California at San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20622854" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/chemistry/metabolism ; Cell Cycle/*physiology ; Cell Line ; Chromatin/metabolism ; Chromosomal Proteins, Non-Histone/chemistry/deficiency/genetics/*metabolism ; DNA-Binding Proteins/chemistry/metabolism ; HeLa Cells ; Histone Demethylases/chemistry/genetics/*metabolism ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/chemistry/*metabolism ; Host Cell Factor C1/genetics/metabolism ; Humans ; Lysine/*metabolism ; Methylation ; Multiprotein Complexes/chemistry/metabolism ; Phosphorylation ; Promoter Regions, Genetic ; Protein Structure, Tertiary ; Transcription Factors/chemistry/deficiency/genetics/*metabolism
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    Structural basis of oligomerization in the stalk region of dynamin-like MxA (2010)
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    Publication Date: 2010-04-30
    Description: The interferon-inducible dynamin-like myxovirus resistance protein 1 (MxA; also called MX1) GTPase is a key mediator of cell-autonomous innate immunity against pathogens such as influenza viruses. MxA partially localizes to COPI-positive membranes of the smooth endoplasmic reticulum-Golgi intermediate compartment. At the point of infection, it redistributes to sites of viral replication and promotes missorting of essential viral constituents. It has been proposed that the middle domain and the GTPase effector domain of dynamin-like GTPases constitute a stalk that mediates oligomerization and transmits conformational changes from the G domain to the target structure; however, the molecular architecture of this stalk has remained elusive. Here we report the crystal structure of the stalk of human MxA, which folds into a four-helical bundle. This structure tightly oligomerizes in the crystal in a criss-cross pattern involving three distinct interfaces and one loop. Mutations in each of these interaction sites interfere with native assembly, oligomerization, membrane binding and antiviral activity of MxA. On the basis of these results, we propose a structural model for dynamin oligomerization and stimulated GTP hydrolysis that is consistent with previous structural predictions and has functional implications for all members of the dynamin family.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Song -- von der Malsburg, Alexander -- Paeschke, Susann -- Behlke, Joachim -- Haller, Otto -- Kochs, Georg -- Daumke, Oliver -- England -- Nature. 2010 May 27;465(7297):502-6. doi: 10.1038/nature08972. Epub 2010 Apr 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max-Delbruck-Centrum for Molecular Medicine, Crystallography, Robert-Rossle-Strasse 10, 13125 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20428112" target="_blank"〉PubMed〈/a〉
    Keywords: Antiviral Agents/chemistry/metabolism/pharmacology ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Dynamins/*chemistry/metabolism ; GTP Phosphohydrolases/metabolism ; GTP-Binding Proteins/*chemistry/genetics/*metabolism/pharmacology ; Guanosine Triphosphate/metabolism ; Humans ; Hydrolysis ; Hydrophobic and Hydrophilic Interactions ; Influenza A Virus, H5N1 Subtype/drug effects/physiology ; Models, Molecular ; Myxovirus Resistance Proteins ; Protein Conformation ; *Protein Multimerization ; Virus Replication/drug effects
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    NRMT is an alpha-N-methyltransferase that methylates RCC1 and retinoblastoma protein (2010)
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    Publication Date: 2010-07-30
    Description: The post-translational methylation of alpha-amino groups was first discovered over 30 years ago on the bacterial ribosomal proteins L16 and L33 (refs 1, 2), but almost nothing is known about the function or enzymology of this modification. Several other bacterial and eukaryotic proteins have since been shown to be alpha-N-methylated. However, the Ran guanine nucleotide-exchange factor, RCC1, is the only protein for which any biological function of alpha-N-methylation has been identified. Methylation-defective mutants of RCC1 have reduced affinity for DNA and cause mitotic defects, but further characterization of this modification has been hindered by ignorance of the responsible methyltransferase. All fungal and animal N-terminally methylated proteins contain a unique N-terminal motif, Met-(Ala/Pro/Ser)-Pro-Lys, indicating that they may be targets of the same, unknown enzyme. The initiating Met is cleaved, and the exposed alpha-amino group is mono-, di- or trimethylated. Here we report the discovery of the first alpha-N-methyltransferase, which we named N-terminal RCC1 methyltransferase (NRMT). Substrate docking and mutational analysis of RCC1 defined the NRMT recognition sequence and enabled the identification of numerous new methylation targets, including SET (also known as TAF-I or PHAPII) and the retinoblastoma protein, RB. Knockdown of NRMT recapitulates the multi-spindle phenotype seen with methylation-defective RCC1 mutants, demonstrating the importance of alpha-N-methylation for normal bipolar spindle formation and chromosome segregation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939154/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939154/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tooley, Christine E Schaner -- Petkowski, Janusz J -- Muratore-Schroeder, Tara L -- Balsbaugh, Jeremy L -- Shabanowitz, Jeffrey -- Sabat, Michal -- Minor, Wladek -- Hunt, Donald F -- Macara, Ian G -- R01 GM050526/GM/NIGMS NIH HHS/ -- R01 GM050526-17/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Aug 26;466(7310):1125-8. doi: 10.1038/nature09343.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, Center for Cell Signaling, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA. ces5g@virginia.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20668449" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/*metabolism ; Cell Line ; Chromosome Segregation ; Gene Knockdown Techniques ; Guanine Nucleotide Exchange Factors/*metabolism ; HeLa Cells ; Histone Chaperones/metabolism ; Humans ; Methyltransferases/chemistry/genetics/*metabolism ; Models, Molecular ; Mutation/genetics ; Nuclear Proteins/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Retinoblastoma Protein/*metabolism ; Spindle Apparatus/metabolism ; Transcription Factors/metabolism
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    A law in time? (2010)
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    Publication Date: 2010-09-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2010 Sep 2;467(7311):7. doi: 10.1038/467007a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20811412" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Embryo Research/*economics/*legislation & jurisprudence ; *Embryonic Stem Cells ; Financing, Government/legislation & jurisprudence ; Humans ; National Institutes of Health (U.S.)/economics/*legislation & jurisprudence ; United States
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    Diseased cells fail to win approval (2010)
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    Publication Date: 2010-06-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wadman, Meredith -- England -- Nature. 2010 Jun 17;465(7300):852. doi: 10.1038/465852a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20559353" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Consent Forms/*ethics/standards ; *Embryonic Stem Cells ; Humans ; National Institutes of Health (U.S.)/*ethics/legislation & ; jurisprudence/standards ; United States
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    Orm family proteins mediate sphingolipid homeostasis (2010)
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    Publication Date: 2010-02-26
    Description: Despite the essential roles of sphingolipids both as structural components of membranes and critical signalling molecules, we have a limited understanding of how cells sense and regulate their levels. Here we reveal the function in sphingolipid metabolism of the ORM genes (known as ORMDL genes in humans)-a conserved gene family that includes ORMDL3, which has recently been identified as a potential risk factor for childhood asthma. Starting from an unbiased functional genomic approach in Saccharomyces cerevisiae, we identify Orm proteins as negative regulators of sphingolipid synthesis that form a conserved complex with serine palmitoyltransferase, the first and rate-limiting enzyme in sphingolipid production. We also define a regulatory pathway in which phosphorylation of Orm proteins relieves their inhibitory activity when sphingolipid production is disrupted. Changes in ORM gene expression or mutations to their phosphorylation sites cause dysregulation of sphingolipid metabolism. Our work identifies the Orm proteins as critical mediators of sphingolipid homeostasis and raises the possibility that sphingolipid misregulation contributes to the development of childhood asthma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877384/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877384/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Breslow, David K -- Collins, Sean R -- Bodenmiller, Bernd -- Aebersold, Ruedi -- Simons, Kai -- Shevchenko, Andrej -- Ejsing, Christer S -- Weissman, Jonathan S -- N01-HV-28179/HV/NHLBI NIH HHS/ -- P50 GM073210/GM/NIGMS NIH HHS/ -- P50 GM073210-06/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Feb 25;463(7284):1048-53. doi: 10.1038/nature08787.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 1700 4th Street, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20182505" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Asthma/metabolism ; Cell Line ; Conserved Sequence ; Fatty Acids, Monounsaturated/pharmacology ; HeLa Cells ; *Homeostasis ; Humans ; Molecular Sequence Data ; *Multigene Family ; Multiprotein Complexes/chemistry/metabolism ; Phosphoric Monoester Hydrolases/genetics/metabolism ; Phosphorylation ; Protein Binding ; Saccharomyces cerevisiae/drug effects/enzymology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/classification/genetics/*metabolism ; Serine C-Palmitoyltransferase/genetics/metabolism ; Sphingolipids/biosynthesis/*metabolism
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    Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses (2010)
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    Publication Date: 2010-03-09
    Description: The tumour suppressor ARF is specifically required for p53 activation under oncogenic stress. Recent studies showed that p53 activation mediated by ARF, but not that induced by DNA damage, acts as a major protection against tumorigenesis in vivo under certain biological settings, suggesting that the ARF-p53 axis has more fundamental functions in tumour suppression than originally thought. Because ARF is a very stable protein in most human cell lines, it has been widely assumed that ARF induction is mediated mainly at the transcriptional level and that activation of the ARF-p53 pathway by oncogenes is a much slower and largely irreversible process by comparison with p53 activation after DNA damage. Here we report that ARF is very unstable in normal human cells but that its degradation is inhibited in cancerous cells. Through biochemical purification, we identified a specific ubiquitin ligase for ARF and named it ULF. ULF interacts with ARF both in vitro and in vivo and promotes the lysine-independent ubiquitylation and degradation of ARF. ULF knockdown stabilizes ARF in normal human cells, triggering ARF-dependent, p53-mediated growth arrest. Moreover, nucleophosmin (NPM) and c-Myc, both of which are commonly overexpressed in cancer cells, are capable of abrogating ULF-mediated ARF ubiquitylation through distinct mechanisms, and thereby promote ARF stabilization in cancer cells. These findings reveal the dynamic feature of the ARF-p53 pathway and suggest that transcription-independent mechanisms are critically involved in ARF regulation during responses to oncogenic stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737736/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3737736/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Delin -- Shan, Jing -- Zhu, Wei-Guo -- Qin, Jun -- Gu, Wei -- P01 CA080058/CA/NCI NIH HHS/ -- P01 CA097403/CA/NCI NIH HHS/ -- R01 CA085533/CA/NCI NIH HHS/ -- R01 CA118561/CA/NCI NIH HHS/ -- R01 CA129627/CA/NCI NIH HHS/ -- R01 CA131439/CA/NCI NIH HHS/ -- England -- Nature. 2010 Mar 25;464(7288):624-7. doi: 10.1038/nature08820. Epub 2010 Mar 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cancer Genetics, and Department of Pathology and Cell Biology College of Physicians & Surgeons, Columbia University, 1130 St Nicholas Avenue, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20208519" target="_blank"〉PubMed〈/a〉
    Keywords: ADP-Ribosylation Factors/*metabolism ; Cell Line ; Fibroblasts/metabolism ; *Gene Expression Regulation ; Humans ; Molecular Sequence Data ; Nuclear Proteins/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; Stress, Physiological/*physiology ; Tumor Suppressor Protein p53/*metabolism ; U937 Cells ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
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    A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells (2010)
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    Publication Date: 2010-09-11
    Description: Dendritic cells serve a key function in host defence, linking innate detection of microbes to activation of pathogen-specific adaptive immune responses. Whether there is cell-intrinsic recognition of human immunodeficiency virus (HIV) by host innate pattern-recognition receptors and subsequent coupling to antiviral T-cell responses is not yet known. Dendritic cells are largely resistant to infection with HIV-1, but facilitate infection of co-cultured T-helper cells through a process of trans-enhancement. Here we show that, when dendritic cell resistance to infection is circumvented, HIV-1 induces dendritic cell maturation, an antiviral type I interferon response and activation of T cells. This innate response is dependent on the interaction of newly synthesized HIV-1 capsid with cellular cyclophilin A (CYPA) and the subsequent activation of the transcription factor IRF3. Because the peptidylprolyl isomerase CYPA also interacts with HIV-1 capsid to promote infectivity, our results indicate that capsid conformation has evolved under opposing selective pressures for infectivity versus furtiveness. Thus, a cell-intrinsic sensor for HIV-1 exists in dendritic cells and mediates an antiviral immune response, but it is not typically engaged owing to the absence of dendritic cell infection. The virulence of HIV-1 may be related to evasion of this response, the manipulation of which may be necessary to generate an effective HIV-1 vaccine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051279/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3051279/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Manel, Nicolas -- Hogstad, Brandon -- Wang, Yaming -- Levy, David E -- Unutmaz, Derya -- Littman, Dan R -- AI28900/AI/NIAID NIH HHS/ -- AI33856/AI/NIAID NIH HHS/ -- R01 AI033856/AI/NIAID NIH HHS/ -- R01 AI033856-16/AI/NIAID NIH HHS/ -- R01AI065303/AI/NIAID NIH HHS/ -- R21 AI084633/AI/NIAID NIH HHS/ -- U54-AI057158/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Sep 9;467(7312):214-7. doi: 10.1038/nature09337.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20829794" target="_blank"〉PubMed〈/a〉
    Keywords: Capsid Proteins/immunology ; Cell Line ; Cyclophilin A/immunology ; Dendritic Cells/cytology/*immunology/metabolism/*virology ; HIV Infections/*immunology/virology ; HIV-1/*immunology/physiology ; Humans ; *Immunity, Innate ; Interferon Regulatory Factor-3/genetics/metabolism ; Lymphocyte Activation ; Monocytes/cytology ; T-Lymphocytes/immunology
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    mTORC1 controls fasting-induced ketogenesis and its modulation by ageing (2010)
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    Publication Date: 2010-12-24
    Description: The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of a mammalian pathway that coordinates cell growth with the availability of nutrients, energy and growth factors. Progress has been made in the identification of mTORC1 pathway components and in understanding their functions in cells, but there is relatively little known about the role of the pathway in vivo. Specifically, we have little knowledge regarding the role mTOCR1 has in liver physiology. In fasted animals, the liver performs numerous functions that maintain whole-body homeostasis, including the production of ketone bodies for peripheral tissues to use as energy sources. Here we show that mTORC1 controls ketogenesis in mice in response to fasting. We find that liver-specific loss of TSC1 (tuberous sclerosis 1), an mTORC1 inhibitor, leads to a fasting-resistant increase in liver size, and to a pronounced defect in ketone body production and ketogenic gene expression on fasting. The loss of raptor (regulatory associated protein of mTOR, complex 1) an essential mTORC1 component, has the opposite effects. In addition, we find that the inhibition of mTORC1 is required for the fasting-induced activation of PPARalpha (peroxisome proliferator activated receptor alpha), the master transcriptional activator of ketogenic genes, and that suppression of NCoR1 (nuclear receptor co-repressor 1), a co-repressor of PPARalpha, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signalling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis, which correlates with an increase in mTORC1 signalling. Moreover, we show that the suppressive effects of mTORC1 activation and ageing on PPARalpha activity and ketone production are not additive, and that mTORC1 inhibition is sufficient to prevent the ageing-induced defect in ketogenesis. Thus, our findings reveal that mTORC1 is a key regulator of PPARalpha function and hepatic ketogenesis and suggest a role for mTORC1 activity in promoting the ageing of the liver.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sengupta, Shomit -- Peterson, Timothy R -- Laplante, Mathieu -- Oh, Stephanie -- Sabatini, David M -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-04/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Dec 23;468(7327):1100-4. doi: 10.1038/nature09584.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21179166" target="_blank"〉PubMed〈/a〉
    Keywords: *Aging ; Animals ; Cell Line ; Fasting/*metabolism ; *Gene Expression Regulation ; Humans ; Ketone Bodies/*biosynthesis/metabolism ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Multiprotein Complexes ; Nuclear Receptor Co-Repressor 1/metabolism ; PPAR alpha/antagonists & inhibitors/metabolism ; Proteins/genetics/*metabolism ; TOR Serine-Threonine Kinases
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    Phosphorylation of MLL by ATR is required for execution of mammalian S-phase checkpoint (2010)
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    Publication Date: 2010-09-08
    Description: Cell cycle checkpoints are implemented to safeguard the genome, avoiding the accumulation of genetic errors. Checkpoint loss results in genomic instability and contributes to the evolution of cancer. Among G1-, S-, G2- and M-phase checkpoints, genetic studies indicate the role of an intact S-phase checkpoint in maintaining genome integrity. Although the basic framework of the S-phase checkpoint in multicellular organisms has been outlined, the mechanistic details remain to be elucidated. Human chromosome-11 band-q23 translocations disrupting the MLL gene lead to poor prognostic leukaemias. Here we assign MLL as a novel effector in the mammalian S-phase checkpoint network and identify checkpoint dysfunction as an underlying mechanism of MLL leukaemias. MLL is phosphorylated at serine 516 by ATR in response to genotoxic stress in the S phase, which disrupts its interaction with, and hence its degradation by, the SCF(Skp2) E3 ligase, leading to its accumulation. Stabilized MLL protein accumulates on chromatin, methylates histone H3 lysine 4 at late replication origins and inhibits the loading of CDC45 to delay DNA replication. Cells deficient in MLL showed radioresistant DNA synthesis and chromatid-type genomic abnormalities, indicative of S-phase checkpoint dysfunction. Reconstitution of Mll(-/-) (Mll also known as Mll1) mouse embryonic fibroblasts with wild-type but not S516A or DeltaSET mutant MLL rescues the S-phase checkpoint defects. Moreover, murine myeloid progenitor cells carrying an Mll-CBP knock-in allele that mimics human t(11;16) leukaemia show a severe radioresistant DNA synthesis phenotype. MLL fusions function as dominant negative mutants that abrogate the ATR-mediated phosphorylation/stabilization of wild-type MLL on damage to DNA, and thus compromise the S-phase checkpoint. Together, our results identify MLL as a key constituent of the mammalian DNA damage response pathway and show that deregulation of the S-phase checkpoint incurred by MLL translocations probably contributes to the pathogenesis of human MLL leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940944/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940944/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Han -- Takeda, Shugaku -- Kumar, Rakesh -- Westergard, Todd D -- Brown, Eric J -- Pandita, Tej K -- Cheng, Emily H-Y -- Hsieh, James J-D -- CA119008/CA/NCI NIH HHS/ -- CA123232/CA/NCI NIH HHS/ -- CA129537/CA/NCI NIH HHS/ -- R01 CA119008/CA/NCI NIH HHS/ -- R01 CA119008-01/CA/NCI NIH HHS/ -- R01 CA119008-02/CA/NCI NIH HHS/ -- R01 CA119008-03/CA/NCI NIH HHS/ -- R01 CA119008-04/CA/NCI NIH HHS/ -- R01 CA119008-05/CA/NCI NIH HHS/ -- England -- Nature. 2010 Sep 16;467(7313):343-6. doi: 10.1038/nature09350. Epub 2010 Sep 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20818375" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/*metabolism ; Cell Line ; Chromatin/metabolism ; DNA Damage ; DNA Replication/physiology ; Genes, Dominant/genetics ; Genomic Instability/physiology ; Histone-Lysine N-Methyltransferase ; Histones/chemistry/metabolism ; Humans ; Leukemia/genetics ; Lysine/metabolism ; Methylation ; Mice ; Myeloid Progenitor Cells/metabolism ; Myeloid-Lymphoid Leukemia Protein/chemistry/deficiency/genetics/*metabolism ; Phosphorylation ; Phosphoserine/metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases/*metabolism ; S Phase/*physiology ; S-Phase Kinase-Associated Proteins/metabolism ; Signal Transduction ; Translocation, Genetic/genetics
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    Maternal Rnf12/RLIM is required for imprinted X-chromosome inactivation in mice (2010)
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    Publication Date: 2010-10-22
    Description: Two forms of X-chromosome inactivation (XCI) ensure the selective silencing of female sex chromosomes during mouse embryogenesis. Imprinted XCI begins with the detection of Xist RNA expression on the paternal X chromosome (Xp) at about the four-cell stage of embryonic development. In the embryonic tissues of the inner cell mass, a random form of XCI occurs in blastocysts that inactivates either Xp or the maternal X chromosome (Xm). Both forms of XCI require the non-coding Xist RNA that coats the inactive X chromosome from which it is expressed. Xist has crucial functions in the silencing of X-linked genes, including Rnf12 (refs 3, 4) encoding the ubiquitin ligase RLIM (RING finger LIM-domain-interacting protein). Here we show, by targeting a conditional knockout of Rnf12 to oocytes where RLIM accumulates to high levels, that the maternal transmission of the mutant X chromosome (Deltam) leads to lethality in female embryos as a result of defective imprinted XCI. We provide evidence that in Deltam female embryos the initial formation of Xist clouds and Xp silencing are inhibited. In contrast, embryonic stem cells lacking RLIM are able to form Xist clouds and silence at least some X-linked genes during random XCI. These results assign crucial functions to the maternal deposit of Rnf12/RLIM for the initiation of imprinted XCI.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967734/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967734/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shin, Jongdae -- Bossenz, Michael -- Chung, Young -- Ma, Hong -- Byron, Meg -- Taniguchi-Ishigaki, Naoko -- Zhu, Xiaochun -- Jiao, Baowei -- Hall, Lisa L -- Green, Michael R -- Jones, Stephen N -- Hermans-Borgmeyer, Irm -- Lawrence, Jeanne B -- Bach, Ingolf -- 5 P30 DK32520/DK/NIDDK NIH HHS/ -- DK32520/DK/NIDDK NIH HHS/ -- GM053234/GM/NIGMS NIH HHS/ -- R01 CA131158/CA/NCI NIH HHS/ -- R01 CA131158-04/CA/NCI NIH HHS/ -- R01 GM033977/GM/NIGMS NIH HHS/ -- R01 GM053234/GM/NIGMS NIH HHS/ -- R01CA131158/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Oct 21;467(7318):977-81. doi: 10.1038/nature09457.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Gene Function and Expression, University of Massachusetts Medical School (UMMS), Worcester, Massachusetts 01605, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20962847" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Congenic ; Blastocyst/metabolism ; Cell Line ; Chromosomes, Mammalian/*genetics ; Embryo Loss/genetics ; Fathers ; Female ; Gene Silencing ; *Genomic Imprinting ; Male ; Mice ; Mice, Transgenic ; *Mothers ; RNA, Long Noncoding ; RNA, Untranslated/genetics ; Repressor Proteins/deficiency/genetics/*metabolism ; Ubiquitin-Protein Ligases ; X Chromosome/*genetics ; X Chromosome Inactivation/*genetics
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    Stem-cell work thrown into limbo (2010)
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    Publication Date: 2010-09-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wadman, Meredith -- England -- Nature. 2010 Sep 2;467(7311):12-3. doi: 10.1038/467012a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20811425" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Embryo Research/*economics/*legislation & jurisprudence ; *Embryonic Stem Cells ; Financing, Government/*legislation & jurisprudence ; Humans
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    Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET (2010)
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    Publication Date: 2010-02-19
    Description: Endogenous retroviruses (ERVs), retrovirus-like elements with long terminal repeats, are widely dispersed in the euchromatic compartment in mammalian cells, comprising approximately 10% of the mouse genome. These parasitic elements are responsible for 〉10% of spontaneous mutations. Whereas DNA methylation has an important role in proviral silencing in somatic and germ-lineage cells, an additional DNA-methylation-independent pathway also functions in embryonal carcinoma and embryonic stem (ES) cells to inhibit transcription of the exogenous gammaretrovirus murine leukaemia virus (MLV). Notably, a recent genome-wide study revealed that ERVs are also marked by histone H3 lysine 9 trimethylation (H3K9me3) and H4K20me3 in ES cells but not in mouse embryonic fibroblasts. However, the role that these marks have in proviral silencing remains unexplored. Here we show that the H3K9 methyltransferase ESET (also called SETDB1 or KMT1E) and the Kruppel-associated box (KRAB)-associated protein 1 (KAP1, also called TRIM28) are required for H3K9me3 and silencing of endogenous and introduced retroviruses specifically in mouse ES cells. Furthermore, whereas ESET enzymatic activity is crucial for HP1 binding and efficient proviral silencing, the H4K20 methyltransferases Suv420h1 and Suv420h2 are dispensable for silencing. Notably, in DNA methyltransferase triple knockout (Dnmt1(-/-)Dnmt3a(-/-)Dnmt3b(-/-)) mouse ES cells, ESET and KAP1 binding and ESET-mediated H3K9me3 are maintained and ERVs are minimally derepressed. We propose that a DNA-methylation-independent pathway involving KAP1 and ESET/ESET-mediated H3K9me3 is required for proviral silencing during the period early in embryogenesis when DNA methylation is dynamically reprogrammed.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Matsui, Toshiyuki -- Leung, Danny -- Miyashita, Hiroki -- Maksakova, Irina A -- Miyachi, Hitoshi -- Kimura, Hiroshi -- Tachibana, Makoto -- Lorincz, Matthew C -- Shinkai, Yoichi -- 77805/Canadian Institutes of Health Research/Canada -- 92090/Canadian Institutes of Health Research/Canada -- England -- Nature. 2010 Apr 8;464(7290):927-31. doi: 10.1038/nature08858. Epub 2010 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Experimental Research Center for Infectious Diseases, Institute for Virus Research, Kyoto University, 53 Shogoin, Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20164836" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; DNA (Cytosine-5-)-Methyltransferase/deficiency/genetics/metabolism ; DNA Methylation/genetics ; Embryonic Stem Cells/*enzymology/metabolism/*virology ; Endogenous Retroviruses/*genetics ; Fibroblasts ; Gene Deletion ; *Gene Silencing ; Histone-Lysine N-Methyltransferase/deficiency/genetics/*metabolism ; Mice ; Nuclear Proteins/metabolism ; Protein Methyltransferases/deficiency/genetics/*metabolism ; Proviruses/*genetics ; Repressor Proteins/metabolism
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    Drug discovery: schistosome treatment (2008)
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    Publication Date: 2008-03-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shadan, Sadaf -- England -- Nature. 2008 Mar 20;452(7185):296. doi: 10.1038/452296b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18354470" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anthelmintics/*pharmacology/therapeutic use/toxicity ; Antioxidants/metabolism ; Cell Line ; *Drug Evaluation, Preclinical ; Drug Resistance ; Humans ; Mice ; Oxadiazoles/*pharmacology/toxicity ; Praziquantel/pharmacology/therapeutic use/toxicity ; Schistosoma mansoni/drug effects/metabolism ; Schistosomiasis/*drug therapy/*parasitology
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    The CRAC channel consists of a tetramer formed by Stim-induced dimerization of Orai dimers (2008)
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    Publication Date: 2008-09-30
    Description: Ca(2+)-release-activated Ca(2+) (CRAC) channels underlie sustained Ca(2+) signalling in lymphocytes and numerous other cells after Ca(2+) liberation from the endoplasmic reticulum (ER). RNA interference screening approaches identified two proteins, Stim and Orai, that together form the molecular basis for CRAC channel activity. Stim senses depletion of the ER Ca(2+) store and physically relays this information by translocating from the ER to junctions adjacent to the plasma membrane, and Orai embodies the pore of the plasma membrane calcium channel. A close interaction between Stim and Orai, identified by co-immunoprecipitation and by Forster resonance energy transfer, is involved in the opening of the Ca(2+) channel formed by Orai subunits. Most ion channels are multimers of pore-forming subunits surrounding a central channel, which are preassembled in the ER and transported in their final stoichiometry to the plasma membrane. Here we show, by biochemical analysis after cross-linking in cell lysates and intact cells and by using non-denaturing gel electrophoresis without cross-linking, that Orai is predominantly a dimer in the plasma membrane under resting conditions. Moreover, single-molecule imaging of green fluorescent protein (GFP)-tagged Orai expressed in Xenopus oocytes showed predominantly two-step photobleaching, again consistent with a dimeric basal state. In contrast, co-expression of GFP-tagged Orai with the carboxy terminus of Stim as a cytosolic protein to activate the Orai channel without inducing Ca(2+) store depletion or clustering of Orai into punctae yielded mostly four-step photobleaching, consistent with a tetrameric stoichiometry of the active Orai channel. Interaction with the C terminus of Stim thus induces Orai dimers to dimerize, forming tetramers that constitute the Ca(2+)-selective pore. This represents a new mechanism in which assembly and activation of the functional ion channel are mediated by the same triggering molecule.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597643/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597643/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Penna, Aubin -- Demuro, Angelo -- Yeromin, Andriy V -- Zhang, Shenyuan L -- Safrina, Olga -- Parker, Ian -- Cahalan, Michael D -- P30 CA062203/CA/NCI NIH HHS/ -- R37 NS014609/NS/NINDS NIH HHS/ -- R37 NS014609-29/NS/NINDS NIH HHS/ -- England -- Nature. 2008 Nov 6;456(7218):116-20. doi: 10.1038/nature07338. Epub 2008 Sep 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and Biophysics, University of California Irvine, California 92697-4561, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18820677" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium Channels/*chemistry/genetics/*metabolism ; Cell Line ; Cross-Linking Reagents ; Drosophila Proteins/*chemistry/genetics/*metabolism ; Drosophila melanogaster/*chemistry/*metabolism ; Humans ; Membrane Proteins/*chemistry/genetics/*metabolism ; Oocytes/metabolism ; Photobleaching ; Protein Multimerization ; Protein Structure, Quaternary ; Xenopus ; Xenopus Proteins/*chemistry/genetics/*metabolism
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    The essential role of the CopN protein in Chlamydia pneumoniae intracellular growth (2008)
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    Publication Date: 2008-10-03
    Description: Bacterial virulence determinants can be identified, according to the molecular Koch's postulates, if inactivation of a gene associated with a suspected virulence trait results in a loss in pathogenicity. This approach is commonly used with genetically tractable organisms. However, the current lack of tools for targeted gene disruptions in obligate intracellular microbial pathogens seriously hampers the identification of their virulence factors. Here we demonstrate an approach to studying potential virulence factors of genetically intractable organisms, such as Chlamydia. Heterologous expression of Chlamydia pneumoniae CopN in yeast and mammalian cells resulted in a cell cycle arrest, presumably owing to alterations in the microtubule cytoskeleton. A screen of a small molecule library identified two compounds that alleviated CopN-induced growth inhibition in yeast. These compounds interfered with C. pneumoniae replication in mammalian cells, presumably by 'knocking out' CopN function, revealing an essential role of CopN in the support of C. pneumoniae growth during infection. This work demonstrates the role of a specific chlamydial protein in virulence. The chemical biology approach described here can be used to identify virulence factors, and the reverse chemical genetic strategy can result in the identification of lead compounds for the development of novel therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673727/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673727/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Jin -- Lesser, Cammie F -- Lory, Stephen -- R01 AI064285/AI/NIAID NIH HHS/ -- R01 AI064285-03/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Nov 6;456(7218):112-5. doi: 10.1038/nature07355. Epub 2008 Oct 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Molecular Genetics, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18830244" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacterial Proteins/antagonists & inhibitors/genetics/*metabolism ; Cell Cycle ; Cell Line ; Chlamydophila pneumoniae/drug effects/genetics/*growth & ; development/*pathogenicity ; Gene Expression ; Genes, Essential ; Heterocyclic Compounds with 4 or More Rings/pharmacology ; Humans ; Intracellular Space/*microbiology ; Microtubules/metabolism ; Saccharomyces cerevisiae/cytology/drug effects/genetics/metabolism ; Virulence/drug effects ; Virulence Factors/antagonists & inhibitors/genetics/*metabolism
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    Pyruvate kinase M2 is a phosphotyrosine-binding protein (2008)
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    Publication Date: 2008-03-14
    Description: Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine-binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 (fetal) isoform of pyruvate kinase (PKM2), binds directly and selectively to tyrosine-phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose-1,6-bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine-binding form of pyruvate kinase is critical for rapid growth in cancer cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Christofk, Heather R -- Vander Heiden, Matthew G -- Wu, Ning -- Asara, John M -- Cantley, Lewis C -- R01 GM056203/GM/NIGMS NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- England -- Nature. 2008 Mar 13;452(7184):181-6. doi: 10.1038/nature06667.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337815" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Site ; Animals ; Catalysis ; Cell Line ; Cell Proliferation/drug effects ; Cells/drug effects/metabolism ; HeLa Cells ; Humans ; Lysine/metabolism ; Models, Molecular ; Peptide Library ; Phosphotyrosine/*metabolism ; Protein Binding ; Proteomics ; Pyruvate Kinase/antagonists & inhibitors/*metabolism ; Substrate Specificity
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    CDK targets Sae2 to control DNA-end resection and homologous recombination (2008)
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    Publication Date: 2008-08-22
    Description: DNA double-strand breaks (DSBs) are repaired by two principal mechanisms: non-homologous end-joining (NHEJ) and homologous recombination (HR). HR is the most accurate DSB repair mechanism but is generally restricted to the S and G2 phases of the cell cycle, when DNA has been replicated and a sister chromatid is available as a repair template. By contrast, NHEJ operates throughout the cell cycle but assumes most importance in G1 (refs 4, 6). The choice between repair pathways is governed by cyclin-dependent protein kinases (CDKs), with a major site of control being at the level of DSB resection, an event that is necessary for HR but not NHEJ, and which takes place most effectively in S and G2 (refs 2, 5). Here we establish that cell-cycle control of DSB resection in Saccharomyces cerevisiae results from the phosphorylation by CDK of an evolutionarily conserved motif in the Sae2 protein. We show that mutating Ser 267 of Sae2 to a non-phosphorylatable residue causes phenotypes comparable to those of a sae2Delta null mutant, including hypersensitivity to camptothecin, defective sporulation, reduced hairpin-induced recombination, severely impaired DNA-end processing and faulty assembly and disassembly of HR factors. Furthermore, a Sae2 mutation that mimics constitutive Ser 267 phosphorylation complements these phenotypes and overcomes the necessity of CDK activity for DSB resection. The Sae2 mutations also cause cell-cycle-stage specific hypersensitivity to DNA damage and affect the balance between HR and NHEJ. These findings therefore provide a mechanistic basis for cell-cycle control of DSB repair and highlight the importance of regulating DSB resection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635538/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2635538/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huertas, Pablo -- Cortes-Ledesma, Felipe -- Sartori, Alessandro A -- Aguilera, Andres -- Jackson, Stephen P -- A5290/Cancer Research UK/United Kingdom -- LSHG-CT-2005-512113/Cancer Research UK/United Kingdom -- England -- Nature. 2008 Oct 2;455(7213):689-92. doi: 10.1038/nature07215. Epub 2008 Aug 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust and Cancer Research UK Gurdon Institute, and Department of Zoology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18716619" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; CDC28 Protein Kinase, S cerevisiae/*metabolism ; Cell Cycle ; Cell Line ; Cell Survival ; Conserved Sequence ; *DNA Breaks, Double-Stranded ; *DNA Repair ; Endodeoxyribonucleases/metabolism ; Endonucleases ; Exodeoxyribonucleases/metabolism ; Humans ; Mutation ; Phosphorylation ; Phosphoserine/metabolism ; Rad52 DNA Repair and Recombination Protein/metabolism ; *Recombination, Genetic ; Saccharomyces cerevisiae/enzymology/*genetics/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism
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    BAX activation is initiated at a novel interaction site (2008)
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    Publication Date: 2008-10-25
    Description: BAX is a pro-apoptotic protein of the BCL-2 family that is stationed in the cytosol until activated by a diversity of stress stimuli to induce cell death. Anti-apoptotic proteins such as BCL-2 counteract BAX-mediated cell death. Although an interaction site that confers survival functionality has been defined for anti-apoptotic proteins, an activation site has not been identified for BAX, rendering its explicit trigger mechanism unknown. We previously developed stabilized alpha-helix of BCL-2 domains (SAHBs) that directly initiate BAX-mediated mitochondrial apoptosis. Here we demonstrate by NMR analysis that BIM SAHB binds BAX at an interaction site that is distinct from the canonical binding groove characterized for anti-apoptotic proteins. The specificity of the human BIM-SAHB-BAX interaction is highlighted by point mutagenesis that disrupts functional activity, confirming that BAX activation is initiated at this novel structural location. Thus, we have now defined a BAX interaction site for direct activation, establishing a new target for therapeutic modulation of apoptosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597110/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597110/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gavathiotis, Evripidis -- Suzuki, Motoshi -- Davis, Marguerite L -- Pitter, Kenneth -- Bird, Gregory H -- Katz, Samuel G -- Tu, Ho-Chou -- Kim, Hyungjin -- Cheng, Emily H-Y -- Tjandra, Nico -- Walensky, Loren D -- 5P01CA92625/CA/NCI NIH HHS/ -- 5R01CA125562/CA/NCI NIH HHS/ -- 5R01CA50239/CA/NCI NIH HHS/ -- K99 HL095929/HL/NHLBI NIH HHS/ -- K99 HL095929-01A1/HL/NHLBI NIH HHS/ -- K99 HL095929-02/HL/NHLBI NIH HHS/ -- R00 HL095929/HL/NHLBI NIH HHS/ -- R01 CA050239/CA/NCI NIH HHS/ -- R01 CA125562/CA/NCI NIH HHS/ -- R01 CA125562-02/CA/NCI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2008 Oct 23;455(7216):1076-81. doi: 10.1038/nature07396.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric Oncology and the Program in Cancer Chemical Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18948948" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Apoptosis ; Apoptosis Regulatory Proteins/chemistry/metabolism ; BH3 Interacting Domain Death Agonist Protein/metabolism ; Cell Line ; *Gene Expression Regulation ; Humans ; Membrane Proteins/chemistry/metabolism ; Mice ; Mutagenesis, Site-Directed ; Mutation/genetics ; Nuclear Magnetic Resonance, Biomolecular ; Protein Binding ; Proto-Oncogene Proteins/chemistry/metabolism ; Sequence Alignment ; bcl-2-Associated X Protein/chemistry/*metabolism
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    Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen (2008)
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    Publication Date: 2008-11-14
    Description: Crosstalk between the oestrogen receptor (ER) and ERBB2/HER-2 pathways has long been implicated in breast cancer aetiology and drug response, yet no direct connection at a transcriptional level has been shown. Here we show that oestrogen-ER and tamoxifen-ER complexes directly repress ERBB2 transcription by means of a cis-regulatory element within the ERBB2 gene in human cell lines. We implicate the paired box 2 gene product (PAX2), in a previously unrecognized role, as a crucial mediator of ER repression of ERBB2 by the anti-cancer drug tamoxifen. We show that PAX2 and the ER co-activator AIB-1/SRC-3 compete for binding and regulation of ERBB2 transcription, the outcome of which determines tamoxifen response in breast cancer cells. The repression of ERBB2 by ER-PAX2 links these two breast cancer subtypes and suggests that aggressive ERBB2-positive tumours can originate from ER-positive luminal tumours by circumventing this repressive mechanism. These data provide mechanistic insight into the molecular basis of endocrine resistance in breast cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920208/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920208/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hurtado, Antoni -- Holmes, Kelly A -- Geistlinger, Timothy R -- Hutcheson, Iain R -- Nicholson, Robert I -- Brown, Myles -- Jiang, Jie -- Howat, William J -- Ali, Simak -- Carroll, Jason S -- P01CA8011105/CA/NCI NIH HHS/ -- R01 DK074967/DK/NIDDK NIH HHS/ -- R01 DK074967-03/DK/NIDDK NIH HHS/ -- R01DK074967/DK/NIDDK NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2008 Dec 4;456(7222):663-6. doi: 10.1038/nature07483. Epub 2008 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19005469" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/drug therapy/genetics/pathology ; Cell Line ; Cell Line, Tumor ; Chromatin Immunoprecipitation ; Drug Resistance, Neoplasm/genetics ; Estrogens/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Gene Silencing ; Genes, erbB-2/*genetics ; Histone Acetyltransferases ; Humans ; Nuclear Receptor Coactivator 3 ; PAX2 Transcription Factor/deficiency/genetics/*metabolism ; Receptor, ErbB-2/*genetics ; Receptors, Estrogen/*metabolism ; Regulatory Sequences, Nucleic Acid/genetics ; Repressor Proteins/metabolism ; Tamoxifen/metabolism/*pharmacology ; Trans-Activators
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    Stem-cell futures (2008)
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    Publication Date: 2008-11-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2008 Nov 20;456(7220):282. doi: 10.1038/456282a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19020565" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; *Federal Government ; Humans ; Leadership ; National Institutes of Health (U.S.)/*organization & administration ; *Stem Cells/cytology ; United States
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    Alternative isoform regulation in human tissue transcriptomes (2008)
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    Publication Date: 2008-11-04
    Description: Through alternative processing of pre-messenger RNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes on the basis of deep sequencing of complementary DNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analyses in which sequence reads are mapped to exon-exon junctions indicated that 92-94% of human genes undergo alternative splicing, 86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that most alternative splicing and alternative cleavage and polyadenylation events vary between tissues, whereas variation between individuals was approximately twofold to threefold less common. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation in regulatory regions and with generation of full-length open reading frames. Patterns of alternative splicing and alternative cleavage and polyadenylation were strongly correlated across tissues, suggesting coordinated regulation of these processes, and sequence conservation of a subset of known regulatory motifs in both alternative introns and 3' untranslated regions suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593745/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2593745/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Eric T -- Sandberg, Rickard -- Luo, Shujun -- Khrebtukova, Irina -- Zhang, Lu -- Mayr, Christine -- Kingsmore, Stephen F -- Schroth, Gary P -- Burge, Christopher B -- R01 GM085319/GM/NIGMS NIH HHS/ -- R01 GM085319-01/GM/NIGMS NIH HHS/ -- R01 HG002439/HG/NHGRI NIH HHS/ -- R01 HG002439-07/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Nov 27;456(7221):470-6. doi: 10.1038/nature07509.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18978772" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/*genetics ; Base Sequence ; Cell Line ; Exons/genetics ; *Gene Expression Profiling ; Humans ; Open Reading Frames/genetics ; Organ Specificity ; Polyadenylation ; Protein Isoforms/*genetics ; RNA, Messenger/*analysis/*genetics ; RNA-Binding Proteins/metabolism ; Repressor Proteins/metabolism
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    Generation of pluripotent stem cells from adult human testis (2008)
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    Publication Date: 2008-10-14
    Description: Human primordial germ cells and mouse neonatal and adult germline stem cells are pluripotent and show similar properties to embryonic stem cells. Here we report the successful establishment of human adult germline stem cells derived from spermatogonial cells of adult human testis. Cellular and molecular characterization of these cells revealed many similarities to human embryonic stem cells, and the germline stem cells produced teratomas after transplantation into immunodeficient mice. The human adult germline stem cells differentiated into various types of somatic cells of all three germ layers when grown under conditions used to induce the differentiation of human embryonic stem cells. We conclude that the generation of human adult germline stem cells from testicular biopsies may provide simple and non-controversial access to individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Conrad, Sabine -- Renninger, Markus -- Hennenlotter, Jorg -- Wiesner, Tina -- Just, Lothar -- Bonin, Michael -- Aicher, Wilhelm -- Buhring, Hans-Jorg -- Mattheus, Ulrich -- Mack, Andreas -- Wagner, Hans-Joachim -- Minger, Stephen -- Matzkies, Matthias -- Reppel, Michael -- Hescheler, Jurgen -- Sievert, Karl-Dietrich -- Stenzl, Arnulf -- Skutella, Thomas -- England -- Nature. 2008 Nov 20;456(7220):344-9. doi: 10.1038/nature07404. Epub 2008 Oct 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Anatomy, Department of Experimental Embryology, Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18849962" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; Biomarkers/metabolism ; Cell Culture Techniques ; Cell Differentiation ; Cell Line ; Cell Lineage ; Cells, Cultured ; Embryonic Stem Cells/cytology/metabolism ; Epigenesis, Genetic ; Gene Expression Profiling ; Humans ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Pluripotent Stem Cells/*cytology/metabolism ; Spermatogonia/cytology/ultrastructure ; Teratoma/pathology ; Testis/*cytology
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    REST maintains self-renewal and pluripotency of embryonic stem cells (2008)
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    Publication Date: 2008-03-26
    Description: The neuronal repressor REST (RE1-silencing transcription factor; also called NRSF) is expressed at high levels in mouse embryonic stem (ES) cells, but its role in these cells is unclear. Here we show that REST maintains self-renewal and pluripotency in mouse ES cells through suppression of the microRNA miR-21. We found that, as with known self-renewal markers, the level of REST expression is much higher in self-renewing mouse ES cells than in differentiating mouse ES (embryoid body, EB) cells. Heterozygous deletion of Rest (Rest+/-) and its short-interfering-RNA-mediated knockdown in mouse ES cells cause a loss of self-renewal-even when these cells are grown under self-renewal conditions-and lead to the expression of markers specific for multiple lineages. Conversely, exogenously added REST maintains self-renewal in mouse EB cells. Furthermore, Rest+/- mouse ES cells cultured under self-renewal conditions express substantially reduced levels of several self-renewal regulators, including Oct4 (also called Pou5f1), Nanog, Sox2 and c-Myc, and exogenously added REST in mouse EB cells maintains the self-renewal phenotypes and expression of these self-renewal regulators. We also show that in mouse ES cells, REST is bound to the gene chromatin of a set of miRNAs that potentially target self-renewal genes. Whereas mouse ES cells and mouse EB cells containing exogenously added REST express lower levels of these miRNAs, EB cells, Rest+/- ES cells and ES cells treated with short interfering RNA targeting Rest express higher levels of these miRNAs. At least one of these REST-regulated miRNAs, miR-21, specifically suppresses the self-renewal of mouse ES cells, corresponding to the decreased expression of Oct4, Nanog, Sox2 and c-Myc. Thus, REST is a newly discovered element of the interconnected regulatory network that maintains the self-renewal and pluripotency of mouse ES cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830094/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830094/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Singh, Sanjay K -- Kagalwala, Mohamedi N -- Parker-Thornburg, Jan -- Adams, Henry -- Majumder, Sadhan -- CA81255/CA/NCI NIH HHS/ -- CA97124/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R01 CA081255/CA/NCI NIH HHS/ -- R01 CA081255-10/CA/NCI NIH HHS/ -- R01 CA097124/CA/NCI NIH HHS/ -- R01 CA097124-07/CA/NCI NIH HHS/ -- England -- Nature. 2008 May 8;453(7192):223-7. doi: 10.1038/nature06863. Epub 2008 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Genetics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18362916" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomarkers ; Cell Differentiation ; Cell Line ; Cell Lineage ; Cell Proliferation ; Chromatin/genetics/metabolism ; Embryonic Stem Cells/*cytology/*metabolism ; Mice ; Mice, Inbred C57BL ; Pluripotent Stem Cells/*cytology/*metabolism ; Repressor Proteins/genetics/*metabolism ; Transcription Factors/deficiency/genetics/*metabolism
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    Preserving cell shape under environmental stress (2008)
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    Publication Date: 2008-02-26
    Description: Maintaining cell shape and tone is crucial for the function and survival of cells and tissues. Mechanotransduction relies on the transformation of minuscule mechanical forces into high-fidelity electrical responses. When mechanoreceptors are stimulated, mechanically sensitive cation channels open and produce an inward transduction current that depolarizes the cell. For this process to operate effectively, the transduction machinery has to retain integrity and remain unfailingly independent of environmental changes. This is particularly challenging for poikilothermic organisms, where changes in temperature in the environment may impact the function of mechanoreceptor neurons. Thus, we wondered how insects whose habitat might quickly vary over several tens of degrees of temperature manage to maintain highly effective mechanical senses. We screened for Drosophila mutants with defective mechanical responses at elevated ambient temperatures, and identified a gene, spam, whose role is to protect the mechanosensory organ from massive cellular deformation caused by heat-induced osmotic imbalance. Here we show that Spam protein forms an extracellular shield that guards mechanosensory neurons from environmental insult. Remarkably, heterologously expressed Spam protein also endowed other cells with superb defence against physically and chemically induced deformation. We studied the mechanical impact of Spam coating and show that spam-coated cells are up to ten times stiffer than uncoated controls. Together, these results help explain how poikilothermic organisms preserve the architecture of critical cells during environmental stress, and illustrate an elegant and simple solution to such challenge.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387185/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2387185/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cook, Boaz -- Hardy, Robert W -- McConnaughey, William B -- Zuker, Charles S -- R01 EY006979/EY/NEI NIH HHS/ -- R01 EY006979-18/EY/NEI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 20;452(7185):361-4. doi: 10.1038/nature06603. Epub 2008 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Departments of Neurobiology and Neurosciences, University of California at San Diego, La Jolla, California 92093-0649, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18297055" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Shape/*drug effects/*physiology ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/*cytology/drug effects/genetics/physiology ; Electrophysiology ; *Environment ; Eye Proteins/genetics/metabolism ; Hot Temperature ; Humidity ; Mechanoreceptors/cytology/physiology ; Mechanotransduction, Cellular/*drug effects/*physiology ; Models, Biological ; Osmotic Pressure ; Stimulation, Chemical ; Stress, Mechanical
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    Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery (2008)
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    Publication Date: 2008-07-11
    Description: Polo-like kinase-1 (PLK1) is an essential mitotic kinase regulating multiple aspects of the cell division process. Activation of PLK1 requires phosphorylation of a conserved threonine residue (Thr 210) in the T-loop of the PLK1 kinase domain, but the kinase responsible for this has not yet been affirmatively identified. Here we show that in human cells PLK1 activation occurs several hours before entry into mitosis, and requires aurora A (AURKA, also known as STK6)-dependent phosphorylation of Thr 210. We find that aurora A can directly phosphorylate PLK1 on Thr 210, and that activity of aurora A towards PLK1 is greatly enhanced by Bora (also known as C13orf34 and FLJ22624), a known cofactor for aurora A (ref. 7). We show that Bora/aurora-A-dependent phosphorylation is a prerequisite for PLK1 to promote mitotic entry after a checkpoint-dependent arrest. Importantly, expression of a PLK1-T210D phospho-mimicking mutant partially overcomes the requirement for aurora A in checkpoint recovery. Taken together, these data demonstrate that the initial activation of PLK1 is a primary function of aurora A.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Macurek, Libor -- Lindqvist, Arne -- Lim, Dan -- Lampson, Michael A -- Klompmaker, Rob -- Freire, Raimundo -- Clouin, Christophe -- Taylor, Stephen S -- Yaffe, Michael B -- Medema, Rene H -- CA112967/CA/NCI NIH HHS/ -- GM-60594/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Sep 4;455(7209):119-23. doi: 10.1038/nature07185. Epub 2008 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, University Medical Center Utrecht, Utrecht 3584CG, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18615013" target="_blank"〉PubMed〈/a〉
    Keywords: Aurora Kinase A ; Aurora Kinases ; Cell Cycle/*physiology ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line ; DNA Damage ; Enzyme Activation ; Humans ; Mitosis ; Molecular Sequence Data ; Phosphorylation ; Phosphothreonine/metabolism ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Proto-Oncogene Proteins/genetics/*metabolism ; Time Factors
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    Induced ncRNAs allosterically modify RNA-binding proteins in cis to inhibit transcription (2008)
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    Publication Date: 2008-05-30
    Description: With the recent recognition of non-coding RNAs (ncRNAs) flanking many genes, a central issue is to obtain a full understanding of their potential roles in regulated gene transcription programmes, possibly through different mechanisms. Here we show that an RNA-binding protein, TLS (for translocated in liposarcoma), serves as a key transcriptional regulatory sensor of DNA damage signals that, on the basis of its allosteric modulation by RNA, specifically binds to and inhibits CREB-binding protein (CBP) and p300 histone acetyltransferase activities on a repressed gene target, cyclin D1 (CCND1) in human cell lines. Recruitment of TLS to the CCND1 promoter to cause gene-specific repression is directed by single-stranded, low-copy-number ncRNA transcripts tethered to the 5' regulatory regions of CCND1 that are induced in response to DNA damage signals. Our data suggest that signal-induced ncRNAs localized to regulatory regions of transcription units can act cooperatively as selective ligands, recruiting and modulating the activities of distinct classes of RNA-binding co-regulators in response to specific signals, providing an unexpected ncRNA/RNA-binding protein-based strategy to integrate transcriptional programmes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823488/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823488/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xiangting -- Arai, Shigeki -- Song, Xiaoyuan -- Reichart, Donna -- Du, Kun -- Pascual, Gabriel -- Tempst, Paul -- Rosenfeld, Michael G -- Glass, Christopher K -- Kurokawa, Riki -- CA097134/CA/NCI NIH HHS/ -- CA52599/CA/NCI NIH HHS/ -- DK074868/DK/NIDDK NIH HHS/ -- DK39949/DK/NIDDK NIH HHS/ -- HL59694/HL/NHLBI NIH HHS/ -- NS34934/NS/NINDS NIH HHS/ -- P30 CA08748/CA/NCI NIH HHS/ -- R01 CA052599/CA/NCI NIH HHS/ -- R01 CA052599-19/CA/NCI NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- R01 HL059694/HL/NHLBI NIH HHS/ -- R01 HL059694-10/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R01 NS034934-20A1/NS/NINDS NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- R37 DK039949-26/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Jul 3;454(7200):126-30. doi: 10.1038/nature06992. Epub 2008 May 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18509338" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; CREB-Binding Protein/antagonists & inhibitors/metabolism ; Cell Line ; Consensus Sequence ; Cyclin D1/genetics ; DNA Damage ; *Down-Regulation ; HeLa Cells ; Histone Acetyltransferases/antagonists & inhibitors/metabolism ; Humans ; Oligonucleotides/genetics ; Promoter Regions, Genetic/genetics ; RNA, Untranslated/genetics/*metabolism ; RNA-Binding Protein FUS/genetics/*metabolism ; *Transcription, Genetic
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    STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling (2008)
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    Publication Date: 2008-08-30
    Description: The cellular innate immune system is essential for recognizing pathogen infection and for establishing effective host defence. But critical molecular determinants responsible for facilitating an appropriate immune response-following infection with DNA and RNA viruses, for example-remain to be identified. Here we report the identification, following expression cloning, of a molecule (STING; stimulator of interferon genes) that appears essential for effective innate immune signalling processes. It comprises five putative transmembrane regions, predominantly resides in the endoplasmic reticulum and is able to activate both NF-kappaB and IRF3 transcription pathways to induce expression of type I interferon (IFN-alpha and IFN-beta ) and exert a potent anti-viral state following expression. In contrast, loss of STING rendered murine embryonic fibroblasts extremely susceptible to negative-stranded virus infection, including vesicular stomatitis virus. Further, STING ablation abrogated the ability of intracellular B-form DNA, as well as members of the herpesvirus family, to induce IFN-beta, but did not significantly affect the Toll-like receptor (TLR) pathway. Yeast two-hybrid and co-immunoprecipitation studies indicated that STING interacts with RIG-I and with SSR2 (also known as TRAPbeta), which is a member of the translocon-associated protein (TRAP) complex required for protein translocation across the endoplasmic reticulum membrane following translation. Ablation by RNA interference of both TRAPbeta and translocon adaptor SEC61beta was subsequently found to inhibit STING's ability to stimulate expression of IFN-beta. Thus, as well as identifying a regulator of innate immune signalling, our results imply a potential role for the translocon in innate signalling pathways activated by select viruses as well as intracellular DNA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804933/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804933/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ishikawa, Hiroki -- Barber, Glen N -- R01 AI079336/AI/NIAID NIH HHS/ -- R01 AI079336-01/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Oct 2;455(7213):674-8. doi: 10.1038/nature07317. Epub 2008 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida 33136, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18724357" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Endoplasmic Reticulum/*metabolism ; Fibroblasts ; Humans ; Immunity, Innate/*immunology ; Interferons/biosynthesis/immunology ; Membrane Proteins/chemistry/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; *Signal Transduction
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    PML targeting eradicates quiescent leukaemia-initiating cells (2008)
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    Publication Date: 2008-05-13
    Description: The existence of a small population of 'cancer-initiating cells' responsible for tumour maintenance has been firmly demonstrated in leukaemia. This concept is currently being tested in solid tumours. Leukaemia-initiating cells, particularly those that are in a quiescent state, are thought to be resistant to chemotherapy and targeted therapies, resulting in disease relapse. Chronic myeloid leukaemia is a paradigmatic haematopoietic stem cell disease in which the leukaemia-initiating-cell pool is not eradicated by current therapy, leading to disease relapse on drug discontinuation. Here we define the critical role of the promyelocytic leukaemia protein (PML) tumour suppressor in haematopoietic stem cell maintenance, and present a new therapeutic approach for targeting quiescent leukaemia-initiating cells and possibly cancer-initiating cells by pharmacological inhibition of PML.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712082/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712082/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ito, Keisuke -- Bernardi, Rosa -- Morotti, Alessandro -- Matsuoka, Sahoko -- Saglio, Giuseppe -- Ikeda, Yasuo -- Rosenblatt, Jacalyn -- Avigan, David E -- Teruya-Feldstein, Julie -- Pandolfi, Pier Paolo -- K99 CA139009/CA/NCI NIH HHS/ -- R00 CA139009/CA/NCI NIH HHS/ -- R37 CA071692/CA/NCI NIH HHS/ -- R37 CA071692-12/CA/NCI NIH HHS/ -- England -- Nature. 2008 Jun 19;453(7198):1072-8. doi: 10.1038/nature07016. Epub 2008 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Department of Medicine, Harvard Medical School, New Research Building, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18469801" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; Arsenicals/pharmacology/therapeutic use ; Cell Line ; Coculture Techniques ; Female ; Gene Expression Regulation, Neoplastic ; Hematopoietic Stem Cells/pathology ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; Neoplastic Stem Cells/metabolism/*pathology ; Nuclear Proteins/antagonists & inhibitors/deficiency/genetics/*metabolism ; Oxides/pharmacology/therapeutic use ; Recurrence ; Regeneration ; Transcription Factors/antagonists & inhibitors/deficiency/genetics/*metabolism ; Tumor Suppressor Proteins/antagonists & ; inhibitors/deficiency/genetics/*metabolism
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    Replication fork movement sets chromatin loop size and origin choice in mammalian cells (2008)
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    Publication Date: 2008-08-22
    Description: Genome stability requires one, and only one, DNA duplication at each S phase. The mechanisms preventing origin firing on newly replicated DNA are well documented, but much less is known about the mechanisms controlling the spacing of initiation events(2,3), namely the completion of DNA replication. Here we show that origin use in Chinese hamster cells depends on both the movement of the replication forks and the organization of chromatin loops. We found that slowing the replication speed triggers the recruitment of latent origins within minutes, allowing the completion of S phase in a timely fashion. When slowly replicating cells are shifted to conditions of fast fork progression, although the decrease in the overall number of active origins occurs within 2 h, the cells still have to go through a complete cell cycle before the efficiency specific to each origin is restored. We observed a strict correlation between replication speed during a given S phase and the size of chromatin loops in the next G1 phase. Furthermore, we found that origins located at or near sites of anchorage of chromatin loops in G1 are activated preferentially in the following S phase. These data suggest a mechanism of origin programming in which replication speed determines the spacing of anchorage regions of chromatin loops, that, in turn, controls the choice of initiation sites.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Courbet, Sylvain -- Gay, Sophie -- Arnoult, Nausica -- Wronka, Gerd -- Anglana, Mauro -- Brison, Olivier -- Debatisse, Michelle -- England -- Nature. 2008 Sep 25;455(7212):557-60. doi: 10.1038/nature07233. Epub 2008 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Curie, 26 rue d'Ulm, 75248 Paris, France; UPMC Univ. Paris 06, F-75005 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18716622" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Chromatin/genetics/*metabolism ; Cricetinae ; Cricetulus ; DNA/biosynthesis/genetics ; DNA Replication/*physiology ; G1 Phase ; *Movement ; Nuclear Matrix/metabolism ; Replication Origin/*genetics ; S Phase ; Time Factors
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    Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma (2008)
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    Publication Date: 2008-10-17
    Description: Neuroblastoma, a tumour derived from the peripheral sympathetic nervous system, is one of the most frequent solid tumours in childhood. It usually occurs sporadically but familial cases are observed, with a subset of cases occurring in association with congenital malformations of the neural crest being linked to germline mutations of the PHOX2B gene. Here we conducted genome-wide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the anaplastic lymphoma kinase (ALK) tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumour DNAs we identified somatic mutations of the ALK kinase domain that mainly clustered in two hotspots. Germline mutations were observed in two neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wild-type ALK, led to a marked decrease of cell proliferation. Altogether, these data identify ALK as a critical player in neuroblastoma development that may hence represent a very attractive therapeutic target in this disease that is still frequently fatal with current treatments.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Janoueix-Lerosey, Isabelle -- Lequin, Delphine -- Brugieres, Laurence -- Ribeiro, Agnes -- de Pontual, Loic -- Combaret, Valerie -- Raynal, Virginie -- Puisieux, Alain -- Schleiermacher, Gudrun -- Pierron, Gaelle -- Valteau-Couanet, Dominique -- Frebourg, Thierry -- Michon, Jean -- Lyonnet, Stanislas -- Amiel, Jeanne -- Delattre, Olivier -- England -- Nature. 2008 Oct 16;455(7215):967-70. doi: 10.1038/nature07398.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Curie, Centre de Recherche, and Inserm, U830, 26 rue d'Ulm, Paris F-75248, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18923523" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Division ; Cell Line ; Cell Line, Tumor ; Child ; Gene Dosage ; Genome, Human/genetics ; Germ-Line Mutation/*genetics ; Humans ; Neuroblastoma/enzymology/*genetics ; Nucleic Acid Hybridization ; Phosphorylation ; Point Mutation/*genetics ; Polymorphism, Single Nucleotide/genetics ; Protein-Tyrosine Kinases/chemistry/deficiency/*genetics/metabolism ; Receptor Protein-Tyrosine Kinases
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    Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection (2008)
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    Publication Date: 2008-08-15
    Description: Human cytomegalovirus (HCMV) is a ubiquitous human herpesvirus that can cause life-threatening disease in the fetus and the immunocompromised host. Upon attachment to the cell, the virus induces robust inflammatory, interferon- and growth-factor-like signalling. The mechanisms facilitating viral entry and gene expression are not clearly understood. Here we show that platelet-derived growth factor-alpha receptor (PDGFR-alpha) is specifically phosphorylated by both laboratory and clinical isolates of HCMV in various human cell types, resulting in activation of the phosphoinositide-3-kinase (PI(3)K) signalling pathway. Upon stimulation by HCMV, tyrosine-phosphorylated PDGFR-alpha associated with the p85 regulatory subunit of PI(3)K and induced protein kinase B (also known as Akt) phosphorylation, similar to the genuine ligand, PDGF-AA. Cells in which PDGFR-alpha was genetically deleted or functionally blocked were non-permissive to HCMV entry, viral gene expression or infectious virus production. Re-introducing human PDGFRA gene into knockout cells restored susceptibility to viral entry and essential viral gene expression. Blockade of receptor function with a humanized PDGFR-alpha blocking antibody (IMC-3G3) or targeted inhibition of its kinase activity with a small molecule (Gleevec) completely inhibited HCMV viral internalization and gene expression in human epithelial, endothelial and fibroblast cells. Viral entry in cells harbouring endogenous PDGFR-alpha was competitively inhibited by pretreatment with PDGF-AA. We further demonstrate that HCMV glycoprotein B directly interacts with PDGFR-alpha, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies inhibit HCMV-induced PDGFR-alpha phosphorylation. Taken together, these data indicate that PDGFR-alpha is a critical receptor required for HCMV infection, and thus a target for novel anti-viral therapies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soroceanu, Liliana -- Akhavan, Armin -- Cobbs, Charles S -- England -- Nature. 2008 Sep 18;455(7211):391-5. doi: 10.1038/nature07209. Epub 2008 Aug 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurosciences, California Pacific Medical Center Research Institute, Suite 220, 475 Brannan Street, San Francisco, California 94107, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18701889" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cytomegalovirus/*physiology ; Cytomegalovirus Infections/*metabolism/*virology ; Enzyme Activation/drug effects ; Gene Expression Regulation, Viral ; Humans ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphorylation ; Phosphotyrosine/metabolism ; Platelet-Derived Growth Factor/metabolism/pharmacology ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, Platelet-Derived Growth Factor alpha/deficiency/genetics/*metabolism ; Signal Transduction ; Viral Envelope Proteins/metabolism ; Virus Internalization
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    Localization and functionality of microsporidian iron-sulphur cluster assembly proteins (2008)
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    Publication Date: 2008-03-04
    Description: Microsporidia are highly specialized obligate intracellular parasites of other eukaryotes (including humans) that show extreme reduction at the molecular, cellular and biochemical level. Although microsporidia have long been considered as early branching eukaryotes that lack mitochondria, they have recently been shown to contain a tiny mitochondrial remnant called a mitosome. The function of the mitosome is unknown, because microsporidians lack the genes for canonical mitochondrial functions, such as aerobic respiration and haem biosynthesis. However, microsporidial genomes encode several components of the mitochondrial iron-sulphur (Fe-S) cluster assembly machinery. Here we provide experimental insights into the metabolic function and localization of these proteins. We cloned, functionally characterized and localized homologues of several central mitochondrial Fe-S cluster assembly components for the microsporidians Encephalitozoon cuniculi and Trachipleistophora hominis. Several microsporidial proteins can functionally replace their yeast counterparts in Fe-S protein biogenesis. In E. cuniculi, the iron (frataxin) and sulphur (cysteine desulphurase, Nfs1) donors and the scaffold protein (Isu1) co-localize with mitochondrial Hsp70 to the mitosome, consistent with it being the functional site for Fe-S cluster biosynthesis. In T. hominis, mitochondrial Hsp70 and the essential sulphur donor (Nfs1) are still in the mitosome, but surprisingly the main pools of Isu1 and frataxin are cytosolic, creating a conundrum of how these key components of Fe-S cluster biosynthesis coordinate their function. Together, our studies identify the essential biosynthetic process of Fe-S protein assembly as a key function of microsporidian mitosomes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldberg, Alina V -- Molik, Sabine -- Tsaousis, Anastasios D -- Neumann, Karina -- Kuhnke, Grit -- Delbac, Frederic -- Vivares, Christian P -- Hirt, Robert P -- Lill, Roland -- Embley, T Martin -- England -- Nature. 2008 Apr 3;452(7187):624-8. doi: 10.1038/nature06606. Epub 2008 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cell and Molecular Biosciences, The Catherine Cookson Building, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18311129" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cloning, Molecular ; Fungal Proteins/genetics/*metabolism ; HSP70 Heat-Shock Proteins/genetics/metabolism ; Iron-Binding Proteins/genetics/metabolism ; Iron-Sulfur Proteins/*biosynthesis/genetics/metabolism ; Microsporidia/cytology/genetics/*metabolism ; Mitochondria/metabolism ; Molecular Sequence Data ; Protein Transport ; Rabbits ; Saccharomyces cerevisiae/cytology/genetics/metabolism
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    Slow shipping hobbles Chinese science (2008)
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    Publication Date: 2008-12-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cyranoski, David -- England -- Nature. 2008 Dec 4;456(7222):550-1. doi: 10.1038/456550a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052587" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; China ; Commerce/economics ; Indicators and Reagents/*supply & distribution ; Mice ; *Postal Service/economics ; Science/economics/*instrumentation ; Time Factors
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    Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex (2008)
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    Publication Date: 2008-07-04
    Description: Neurotrophins (NTs) are important regulators for the survival, differentiation and maintenance of different peripheral and central neurons. NTs bind to two distinct classes of glycosylated receptor: the p75 neurotrophin receptor (p75(NTR)) and tyrosine kinase receptors (Trks). Whereas p75(NTR) binds to all NTs, the Trk subtypes are specific for each NT. The question of whether NTs stimulate p75(NTR) by inducing receptor homodimerization is still under debate. Here we report the 2.6-A resolution crystal structure of neurotrophin-3 (NT-3) complexed to the ectodomain of glycosylated p75(NTR). In contrast to the previously reported asymmetric complex structure, which contains a dimer of nerve growth factor (NGF) bound to a single ectodomain of deglycosylated p75(NTR) (ref. 3), we show that NT-3 forms a central homodimer around which two glycosylated p75(NTR) molecules bind symmetrically. Symmetrical binding occurs along the NT-3 interfaces, resulting in a 2:2 ligand-receptor cluster. A comparison of the symmetrical and asymmetric structures reveals significant differences in ligand-receptor interactions and p75(NTR) conformations. Biochemical experiments indicate that both NT-3 and NGF bind to p75(NTR) with 2:2 stoichiometry in solution, whereas the 2:1 complexes are the result of artificial deglycosylation. We therefore propose that the symmetrical 2:2 complex reflects a native state of p75(NTR) activation at the cell surface. These results provide a model for NTs-p75(NTR) recognition and signal generation, as well as insights into coordination between p75(NTR) and Trks.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gong, Yong -- Cao, Peng -- Yu, Hong-jun -- Jiang, Tao -- England -- Nature. 2008 Aug 7;454(7205):789-93. doi: 10.1038/nature07089. Epub 2008 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Key Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18596692" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Crystallography, X-Ray ; Dimerization ; Glycosylation ; Humans ; Ligands ; Models, Molecular ; Neurotrophin 3/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Rats ; Receptor, Nerve Growth Factor/*chemistry/genetics/*metabolism ; Spodoptera
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    Identification of a serotonin/glutamate receptor complex implicated in psychosis (2008)
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    Publication Date: 2008-02-26
    Description: The psychosis associated with schizophrenia is characterized by alterations in sensory processing and perception. Some antipsychotic drugs were identified by their high affinity for serotonin 5-HT2A receptors (2AR). Drugs that interact with metabotropic glutamate receptors (mGluR) also have potential for the treatment of schizophrenia. The effects of hallucinogenic drugs, such as psilocybin and lysergic acid diethylamide, require the 2AR and resemble some of the core symptoms of schizophrenia. Here we show that the mGluR2 interacts through specific transmembrane helix domains with the 2AR, a member of an unrelated G-protein-coupled receptor family, to form functional complexes in brain cortex. The 2AR-mGluR2 complex triggers unique cellular responses when targeted by hallucinogenic drugs, and activation of mGluR2 abolishes hallucinogen-specific signalling and behavioural responses. In post-mortem human brain from untreated schizophrenic subjects, the 2AR is upregulated and the mGluR2 is downregulated, a pattern that could predispose to psychosis. These regulatory changes indicate that the 2AR-mGluR2 complex may be involved in the altered cortical processes of schizophrenia, and this complex is therefore a promising new target for the treatment of psychosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743172/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743172/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gonzalez-Maeso, Javier -- Ang, Rosalind L -- Yuen, Tony -- Chan, Pokman -- Weisstaub, Noelia V -- Lopez-Gimenez, Juan F -- Zhou, Mingming -- Okawa, Yuuya -- Callado, Luis F -- Milligan, Graeme -- Gingrich, Jay A -- Filizola, Marta -- Meana, J Javier -- Sealfon, Stuart C -- G9811527/Medical Research Council/United Kingdom -- P01 DA012923/DA/NIDA NIH HHS/ -- P01 DA012923-06A10004/DA/NIDA NIH HHS/ -- T32 DA007135/DA/NIDA NIH HHS/ -- T32 DA007135-25S1/DA/NIDA NIH HHS/ -- T32 GM062754/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Mar 6;452(7183):93-7. doi: 10.1038/nature06612. Epub 2008 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA. javier.maeso@mssm.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18297054" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/cytology/metabolism ; Cell Line ; Cells, Cultured ; Down-Regulation ; Hallucinogens/metabolism/pharmacology ; Humans ; Mice ; Models, Molecular ; Multiprotein Complexes/chemistry/genetics/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Psychotic Disorders/drug therapy/genetics/*metabolism ; Receptor, Serotonin, 5-HT2A/analysis/deficiency/genetics/*metabolism ; Receptors, Metabotropic Glutamate/analysis/antagonists & ; inhibitors/genetics/*metabolism ; Schizophrenia/metabolism ; Signal Transduction/drug effects ; Up-Regulation
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    Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels (2008)
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    Publication Date: 2008-04-15
    Description: From worm to man, many odorant signals are perceived by the binding of volatile ligands to odorant receptors that belong to the G-protein-coupled receptor (GPCR) family. They couple to heterotrimeric G-proteins, most of which induce cAMP production. This second messenger then activates cyclic-nucleotide-gated ion channels to depolarize the olfactory receptor neuron, thus providing a signal for further neuronal processing. Recent findings, however, have challenged this concept of odorant signal transduction in insects, because their odorant receptors, which lack any sequence similarity to other GPCRs, are composed of conventional odorant receptors (for example, Or22a), dimerized with a ubiquitously expressed chaperone protein, such as Or83b in Drosophila. Or83b has a structure akin to GPCRs, but has an inverted orientation in the plasma membrane. However, G proteins are expressed in insect olfactory receptor neurons, and olfactory perception is modified by mutations affecting the cAMP transduction pathway. Here we show that application of odorants to mammalian cells co-expressing Or22a and Or83b results in non-selective cation currents activated by means of an ionotropic and a metabotropic pathway, and a subsequent increase in the intracellular Ca(2+) concentration. Expression of Or83b alone leads to functional ion channels not directly responding to odorants, but being directly activated by intracellular cAMP or cGMP. Insect odorant receptors thus form ligand-gated channels as well as complexes of odorant-sensing units and cyclic-nucleotide-activated non-selective cation channels. Thereby, they provide rapid and transient as well as sensitive and prolonged odorant signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wicher, Dieter -- Schafer, Ronny -- Bauernfeind, Rene -- Stensmyr, Marcus C -- Heller, Regine -- Heinemann, Stefan H -- Hansson, Bill S -- England -- Nature. 2008 Apr 24;452(7190):1007-11. doi: 10.1038/nature06861. Epub 2008 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Evolutionary Neuroethology, Max Planck Institute for Chemical Ecology, Hans-Knoll-St 8, D-07745 Jena, Germany. dwicher@ice.mpg.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18408711" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Butyrates/pharmacology ; Calcium/metabolism ; Cell Line ; Cyclic AMP/metabolism/pharmacology ; Drosophila Proteins/chemistry/genetics/*metabolism ; *Drosophila melanogaster ; Electric Conductivity ; GTP-Binding Protein alpha Subunits, Gs/metabolism ; Humans ; Ion Channel Gating/*drug effects ; Ligands ; Nucleotides, Cyclic/metabolism/*pharmacology ; Odors/analysis ; Patch-Clamp Techniques ; Receptors, Odorant/chemistry/genetics/*metabolism ; Signal Transduction/drug effects
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    Haem homeostasis is regulated by the conserved and concerted functions of HRG-1 proteins (2008)
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    Publication Date: 2008-04-18
    Description: Haems are metalloporphyrins that serve as prosthetic groups for various biological processes including respiration, gas sensing, xenobiotic detoxification, cell differentiation, circadian clock control, metabolic reprogramming and microRNA processing. With a few exceptions, haem is synthesized by a multistep biosynthetic pathway comprising defined intermediates that are highly conserved throughout evolution. Despite our extensive knowledge of haem biosynthesis and degradation, the cellular pathways and molecules that mediate intracellular haem trafficking are unknown. The experimental setback in identifying haem trafficking pathways has been the inability to dissociate the highly regulated cellular synthesis and degradation of haem from intracellular trafficking events. Caenorhabditis elegans and related helminths are natural haem auxotrophs that acquire environmental haem for incorporation into haemoproteins, which have vertebrate orthologues. Here we show, by exploiting this auxotrophy to identify HRG-1 proteins in C. elegans, that these proteins are essential for haem homeostasis and normal development in worms and vertebrates. Depletion of hrg-1, or its paralogue hrg-4, in worms results in the disruption of organismal haem sensing and an abnormal response to haem analogues. HRG-1 and HRG-4 are previously unknown transmembrane proteins, which reside in distinct intracellular compartments. Transient knockdown of hrg-1 in zebrafish leads to hydrocephalus, yolk tube malformations and, most strikingly, profound defects in erythropoiesis-phenotypes that are fully rescued by worm HRG-1. Human and worm proteins localize together, and bind and transport haem, thus establishing an evolutionarily conserved function for HRG-1. These findings reveal conserved pathways for cellular haem trafficking in animals that define the model for eukaryotic haem transport. Thus, uncovering the mechanisms of haem transport in C. elegans may provide insights into human disorders of haem metabolism and reveal new drug targets for developing anthelminthics to combat worm infestations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058867/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058867/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rajagopal, Abbhirami -- Rao, Anita U -- Amigo, Julio -- Tian, Meng -- Upadhyay, Sanjeev K -- Hall, Caitlin -- Uhm, Suji -- Mathew, M K -- Fleming, Mark D -- Paw, Barry H -- Krause, Michael -- Hamza, Iqbal -- R01 DK074797/DK/NIDDK NIH HHS/ -- R01 DK074797-01/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2008 Jun 19;453(7198):1127-31. doi: 10.1038/nature06934. Epub 2008 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Animal & Avian Sciences, University of Maryland, College Park, Maryland 20742, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18418376" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Transport/drug effects ; Caenorhabditis elegans/genetics/*metabolism ; Caenorhabditis elegans Proteins/genetics/*metabolism ; Cell Line ; Erythropoiesis ; Heme/*metabolism/pharmacology ; Hemeproteins/genetics/*metabolism ; *Homeostasis ; Humans ; Metalloporphyrins/metabolism ; Zebrafish/embryology/genetics/*metabolism ; Zebrafish Proteins/genetics/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    An endogenous small interfering RNA pathway in Drosophila (2008)
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    Publication Date: 2008-05-09
    Description: Drosophila endogenous small RNAs are categorized according to their mechanisms of biogenesis and the Argonaute protein to which they bind. MicroRNAs are a class of ubiquitously expressed RNAs of approximately 22 nucleotides in length, which arise from structured precursors through the action of Drosha-Pasha and Dicer-1-Loquacious complexes. These join Argonaute-1 to regulate gene expression. A second endogenous small RNA class, the Piwi-interacting RNAs, bind Piwi proteins and suppress transposons. Piwi-interacting RNAs are restricted to the gonad, and at least a subset of these arises by Piwi-catalysed cleavage of single-stranded RNAs. Here we show that Drosophila generates a third small RNA class, endogenous small interfering RNAs, in both gonadal and somatic tissues. Production of these RNAs requires Dicer-2, but a subset depends preferentially on Loquacious rather than the canonical Dicer-2 partner, R2D2 (ref. 14). Endogenous small interfering RNAs arise both from convergent transcription units and from structured genomic loci in a tissue-specific fashion. They predominantly join Argonaute-2 and have the capacity, as a class, to target both protein-coding genes and mobile elements. These observations expand the repertoire of small RNAs in Drosophila, adding a class that blurs distinctions based on known biogenesis mechanisms and functional roles.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895258/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2895258/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Czech, Benjamin -- Malone, Colin D -- Zhou, Rui -- Stark, Alexander -- Schlingeheyde, Catherine -- Dus, Monica -- Perrimon, Norbert -- Kellis, Manolis -- Wohlschlegel, James A -- Sachidanandam, Ravi -- Hannon, Gregory J -- Brennecke, Julius -- U01 HG004264/HG/NHGRI NIH HHS/ -- U01 HG004264-02/HG/NHGRI NIH HHS/ -- U54 HG004555/HG/NHGRI NIH HHS/ -- U54 HG004555-01/HG/NHGRI NIH HHS/ -- U54 HG004570/HG/NHGRI NIH HHS/ -- U54 HG004570-01/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Jun 5;453(7196):798-802. doi: 10.1038/nature07007. Epub 2008 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18463631" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins ; Cell Line ; Drosophila Proteins/genetics/metabolism ; Drosophila melanogaster/cytology/enzymology/*genetics/metabolism ; Protein Binding ; RNA Helicases/metabolism ; *RNA Interference ; RNA, Small Interfering/biosynthesis/genetics/*metabolism ; RNA-Binding Proteins/metabolism ; RNA-Induced Silencing Complex/genetics/metabolism ; Retroelements/genetics ; Ribonuclease III
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    Drosophila endogenous small RNAs bind to Argonaute 2 in somatic cells (2008)
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    Publication Date: 2008-05-09
    Description: RNA silencing is a conserved mechanism in which small RNAs trigger various forms of sequence-specific gene silencing by guiding Argonaute complexes to target RNAs by means of base pairing. RNA silencing is thought to have evolved as a form of nucleic-acid-based immunity to inactivate viruses and transposable elements. Although the activity of transposable elements in animals has been thought largely to be restricted to the germ line, recent studies have shown that they may also actively transpose in somatic cells, creating somatic mosaicism in animals. In the Drosophila germ line, Piwi-interacting RNAs arise from repetitive intergenic elements including retrotransposons by a Dicer-independent pathway and function through the Piwi subfamily of Argonautes to ensure silencing of retrotransposons. Here we show that, in cultured Drosophila S2 cells, Argonaute 2 (AGO2), an AGO subfamily member of Argonautes, associates with endogenous small RNAs of 20-22 nucleotides in length, which we have collectively named endogenous short interfering RNAs (esiRNAs). esiRNAs can be divided into two groups: one that mainly corresponds to a subset of retrotransposons, and the other that arises from stem-loop structures. esiRNAs are produced in a Dicer-2-dependent manner from distinctive genomic loci, are modified at their 3' ends and can direct AGO2 to cleave target RNAs. Mutations in Dicer-2 caused an increase in retrotransposon transcripts. Together, our findings indicate that different types of small RNAs and Argonautes are used to repress retrotransposons in germline and somatic cells in Drosophila.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kawamura, Yoshinori -- Saito, Kuniaki -- Kin, Taishin -- Ono, Yukiteru -- Asai, Kiyoshi -- Sunohara, Takafumi -- Okada, Tomoko N -- Siomi, Mikiko C -- Siomi, Haruhiko -- England -- Nature. 2008 Jun 5;453(7196):793-7. doi: 10.1038/nature06938. Epub 2008 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Genome Research, University of Tokushima, Tokushima 770-8503, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18463636" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins ; Cell Line ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*cytology/enzymology/genetics/*metabolism ; Eukaryotic Initiation Factors ; Germ Cells/metabolism ; Mosaicism ; Polymerase Chain Reaction ; Protein Binding ; RNA Helicases/genetics/metabolism ; RNA Interference ; RNA, Small Interfering/genetics/*metabolism ; RNA-Induced Silencing Complex/*metabolism ; Retroelements/genetics ; Ribonuclease III
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    The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla (2008)
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    Publication Date: 2008-09-17
    Description: Hedgehog (Hh) proteins specify tissue pattern in metazoan embryos by forming gradients that emanate from discrete sites of expression and elicit concentration-dependent cellular differentiation or proliferation responses. Cellular responses to Hh and the movement of Hh through tissues are both precisely regulated, and abnormal Hh signalling has been implicated in human birth defects and cancer. Hh signalling is mediated by its amino-terminal domain (HhN), which is dually lipidated and secreted as part of a multivalent lipoprotein particle. Reception of the HhN signal is modulated by several cell-surface proteins on responding cells, including Patched (Ptc), Smoothened (Smo), Ihog (known as CDO or CDON in mammals) and the vertebrate-specific proteins Hip (also known as Hhip) and Gas1 (ref. 11). Drosophila Ihog and its vertebrate homologues CDO and BOC contain multiple immunoglobulin and fibronectin type III (FNIII) repeats, and the first FNIII repeat of Ihog binds Drosophila HhN in a heparin-dependent manner. Surprisingly, pull-down experiments suggest that a mammalian Sonic hedgehog N-terminal domain (ShhN) binds a non-orthologous FNIII repeat of CDO. Here we report biochemical, biophysical and X-ray structural studies of a complex between ShhN and the third FNIII repeat of CDO. We show that the ShhN-CDO interaction is completely unlike the HhN-Ihog interaction and requires calcium, which binds at a previously undetected site on ShhN. This site is conserved in nearly all Hh proteins and is a hotspot for mediating interactions between ShhN and CDO, Ptc, Hip and Gas1. Mutations in vertebrate Hh proteins causing holoprosencephaly and brachydactyly type A1 map to this calcium-binding site and disrupt interactions with these partners.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679680/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2679680/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McLellan, Jason S -- Zheng, Xiaoyan -- Hauk, Glenn -- Ghirlando, Rodolfo -- Beachy, Philip A -- Leahy, Daniel J -- R01 HD055545/HD/NICHD NIH HHS/ -- Z99 DK999999/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Oct 16;455(7215):979-83. doi: 10.1038/nature07358. Epub 2008 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18794898" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Calcium/metabolism ; Cell Adhesion Molecules/chemistry/metabolism ; Cell Cycle Proteins/chemistry/metabolism ; Cell Line ; *Conserved Sequence ; Crystallography, X-Ray ; Drosophila Proteins/*chemistry/*metabolism ; Drosophila melanogaster/chemistry ; Fibronectins/chemistry ; GPI-Linked Proteins ; Hedgehog Proteins/*chemistry/genetics/*metabolism ; Humans ; Immunoglobulin G/chemistry/metabolism ; Membrane Glycoproteins/*chemistry/*metabolism ; Membrane Proteins/chemistry/metabolism ; Mice ; Models, Molecular ; Protein Binding/genetics ; Protein Structure, Tertiary ; Receptors, Cell Surface/*chemistry/*metabolism ; *Sequence Homology, Amino Acid ; Signal Transduction ; Tumor Suppressor Proteins/chemistry/metabolism
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    Synergistic response to oncogenic mutations defines gene class critical to cancer phenotype (2008)
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    Publication Date: 2008-05-27
    Description: Understanding the molecular underpinnings of cancer is of critical importance to the development of targeted intervention strategies. Identification of such targets, however, is notoriously difficult and unpredictable. Malignant cell transformation requires the cooperation of a few oncogenic mutations that cause substantial reorganization of many cell features and induce complex changes in gene expression patterns. Genes critical to this multifaceted cellular phenotype have therefore only been identified after signalling pathway analysis or on an ad hoc basis. Our observations that cell transformation by cooperating oncogenic lesions depends on synergistic modulation of downstream signalling circuitry suggest that malignant transformation is a highly cooperative process, involving synergy at multiple levels of regulation, including gene expression. Here we show that a large proportion of genes controlled synergistically by loss-of-function p53 and Ras activation are critical to the malignant state of murine and human colon cells. Notably, 14 out of 24 'cooperation response genes' were found to contribute to tumour formation in gene perturbation experiments. In contrast, only 1 in 14 perturbations of the genes responding in a non-synergistic manner had a similar effect. Synergistic control of gene expression by oncogenic mutations thus emerges as an underlying key to malignancy, and provides an attractive rationale for identifying intervention targets in gene networks downstream of oncogenic gain- and loss-of-function mutations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613942/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2613942/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McMurray, Helene R -- Sampson, Erik R -- Compitello, George -- Kinsey, Conan -- Newman, Laurel -- Smith, Bradley -- Chen, Shaw-Ree -- Klebanov, Lev -- Salzman, Peter -- Yakovlev, Andrei -- Land, Hartmut -- CA120317/CA/NCI NIH HHS/ -- CA90663/CA/NCI NIH HHS/ -- GM075299/GM/NIGMS NIH HHS/ -- K99 LM009477/LM/NLM NIH HHS/ -- K99 LM009477-01A1/LM/NLM NIH HHS/ -- R01 CA090663/CA/NCI NIH HHS/ -- R01 CA090663-03/CA/NCI NIH HHS/ -- R01 CA090663-04/CA/NCI NIH HHS/ -- R01 CA090663-05/CA/NCI NIH HHS/ -- R01 CA120317/CA/NCI NIH HHS/ -- R01 CA120317-01A1/CA/NCI NIH HHS/ -- R01 CA120317-02/CA/NCI NIH HHS/ -- R01 GM075299-01/GM/NIGMS NIH HHS/ -- R01 GM075299-02/GM/NIGMS NIH HHS/ -- R01 GM075299-03/GM/NIGMS NIH HHS/ -- R01 GM075299-03S1/GM/NIGMS NIH HHS/ -- T32 CA009363/CA/NCI NIH HHS/ -- T32 CA009363-25/CA/NCI NIH HHS/ -- T32 CA09363/CA/NCI NIH HHS/ -- England -- Nature. 2008 Jun 19;453(7198):1112-6. doi: 10.1038/nature06973. Epub 2008 May 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18500333" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Transformation, Neoplastic/*genetics ; Colon/cytology/pathology ; Colonic Neoplasms/*genetics ; Gene Expression Regulation, Neoplastic ; Genes, p53/genetics ; Genes, ras/genetics ; Genotype ; Humans ; Mice ; Mice, Nude ; Mutation/*genetics ; Neoplasm Transplantation ; Oncogenes/*genetics ; Phenotype
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    A role for VEGF as a negative regulator of pericyte function and vessel maturation (2008)
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    Publication Date: 2008-11-11
    Description: Angiogenesis does not only depend on endothelial cell invasion and proliferation: it also requires pericyte coverage of vascular sprouts for vessel stabilization. These processes are coordinated by vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) through their cognate receptors on endothelial cells and vascular smooth muscle cells (VSMCs), respectively. PDGF induces neovascularization by priming VSMCs/pericytes to release pro-angiogenic mediators. Although VEGF directly stimulates endothelial cell proliferation and migration, its role in pericyte biology is less clear. Here we define a role for VEGF as an inhibitor of neovascularization on the basis of its capacity to disrupt VSMC function. Specifically, under conditions of PDGF-mediated angiogenesis, VEGF ablates pericyte coverage of nascent vascular sprouts, leading to vessel destabilization. At the molecular level, VEGF-mediated activation of VEGF-R2 suppresses PDGF-Rbeta signalling in VSMCs through the assembly of a previously undescribed receptor complex consisting of PDGF-Rbeta and VEGF-R2. Inhibition of VEGF-R2 not only prevents assembly of this receptor complex but also restores angiogenesis in tissues exposed to both VEGF and PDGF. Finally, genetic deletion of tumour cell VEGF disrupts PDGF-Rbeta/VEGF-R2 complex formation and increases tumour vessel maturation. These findings underscore the importance of VSMCs/pericytes in neovascularization and reveal a dichotomous role for VEGF and VEGF-R2 signalling as both a promoter of endothelial cell function and a negative regulator of VSMCs and vessel maturation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605188/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605188/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Greenberg, Joshua I -- Shields, David J -- Barillas, Samuel G -- Acevedo, Lisette M -- Murphy, Eric -- Huang, Jianhua -- Scheppke, Lea -- Stockmann, Christian -- Johnson, Randall S -- Angle, Niren -- Cheresh, David A -- GM 68524/GM/NIGMS NIH HHS/ -- P01 CA078045/CA/NCI NIH HHS/ -- P01 CA078045-050004/CA/NCI NIH HHS/ -- P01 CA078045-100004/CA/NCI NIH HHS/ -- P01 CA078045-109001/CA/NCI NIH HHS/ -- R01 CA095262/CA/NCI NIH HHS/ -- R01 CA095262-06/CA/NCI NIH HHS/ -- R01 CA118165/CA/NCI NIH HHS/ -- R01 HL078912/HL/NHLBI NIH HHS/ -- R01 HL078912-04/HL/NHLBI NIH HHS/ -- R21 CA129660/CA/NCI NIH HHS/ -- R21 CA129660-02/CA/NCI NIH HHS/ -- R37 CA050286/CA/NCI NIH HHS/ -- R37 CA050286-19/CA/NCI NIH HHS/ -- R37 CA050286-20/CA/NCI NIH HHS/ -- R37-CA082515/CA/NCI NIH HHS/ -- R37-CA50286/CA/NCI NIH HHS/ -- England -- Nature. 2008 Dec 11;456(7223):809-13. doi: 10.1038/nature07424. Epub 2008 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Surgery, School of Medicine, Moore's UCSD Cancer Center, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18997771" target="_blank"〉PubMed〈/a〉
    Keywords: Angiogenesis Inhibitors/pharmacology ; Animals ; Blood Vessels/*metabolism ; Cell Line ; Cells, Cultured ; Fibrosarcoma/blood supply ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Neovascularization, Physiologic/drug effects/*physiology ; Pericytes/drug effects/*metabolism ; Platelet-Derived Growth Factor/*metabolism/pharmacology ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Receptors, Vascular Endothelial Growth Factor/metabolism ; Signal Transduction ; Vascular Endothelial Growth Factor A/*metabolism
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    Molecular basis of xeroderma pigmentosum group C DNA recognition by engineered meganucleases (2008)
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    Publication Date: 2008-11-07
    Description: Xeroderma pigmentosum is a monogenic disease characterized by hypersensitivity to ultraviolet light. The cells of xeroderma pigmentosum patients are defective in nucleotide excision repair, limiting their capacity to eliminate ultraviolet-induced DNA damage, and resulting in a strong predisposition to develop skin cancers. The use of rare cutting DNA endonucleases-such as homing endonucleases, also known as meganucleases-constitutes one possible strategy for repairing DNA lesions. Homing endonucleases have emerged as highly specific molecular scalpels that recognize and cleave DNA sites, promoting efficient homologous gene targeting through double-strand-break-induced homologous recombination. Here we describe two engineered heterodimeric derivatives of the homing endonuclease I-CreI, produced by a semi-rational approach. These two molecules-Amel3-Amel4 and Ini3-Ini4-cleave DNA from the human XPC gene (xeroderma pigmentosum group C), in vitro and in vivo. Crystal structures of the I-CreI variants complexed with intact and cleaved XPC target DNA suggest that the mechanism of DNA recognition and cleavage by the engineered homing endonucleases is similar to that of the wild-type I-CreI. Furthermore, these derivatives induced high levels of specific gene targeting in mammalian cells while displaying no obvious genotoxicity. Thus, homing endonucleases can be designed to recognize and cleave the DNA sequences of specific genes, opening up new possibilities for genome engineering and gene therapy in xeroderma pigmentosum patients whose illness can be treated ex vivo.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Redondo, Pilar -- Prieto, Jesus -- Munoz, Ines G -- Alibes, Andreu -- Stricher, Francois -- Serrano, Luis -- Cabaniols, Jean-Pierre -- Daboussi, Fayza -- Arnould, Sylvain -- Perez, Christophe -- Duchateau, Philippe -- Paques, Frederic -- Blanco, Francisco J -- Montoya, Guillermo -- England -- Nature. 2008 Nov 6;456(7218):107-11. doi: 10.1038/nature07343.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Macromolecular Crystallography Group, Spanish National Cancer Research Centre (CNIO), c/Melchor Fdez. Almagro 3, 28029 Madrid, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18987743" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CHO Cells ; Cell Line ; Cricetinae ; Cricetulus ; Crystallography, X-Ray ; DNA/chemistry/*genetics/*metabolism ; DNA Repair ; DNA Restriction Enzymes/*chemistry/genetics/*metabolism/toxicity ; DNA-Binding Proteins/*genetics ; Enzyme Stability ; *Genetic Engineering ; Humans ; Models, Molecular ; Phosphorylation ; Protein Multimerization ; Substrate Specificity ; Xeroderma Pigmentosum/*genetics
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    DBC1 is a negative regulator of SIRT1 (2008)
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    Publication Date: 2008-02-01
    Description: The NAD-dependent protein deacetylase Sir2 (silent information regulator 2) regulates lifespan in several organisms. SIRT1, the mammalian orthologue of yeast Sir2, participates in various cellular functions and possibly tumorigenesis. Whereas the cellular functions of SIRT1 have been extensively investigated, less is known about the regulation of SIRT1 activity. Here we show that Deleted in Breast Cancer-1 (DBC1), initially cloned from a region (8p21) homozygously deleted in breast cancers, forms a stable complex with SIRT1. DBC1 directly interacts with SIRT1 and inhibits SIRT1 activity in vitro and in vivo. Downregulation of DBC1 expression potentiates SIRT1-dependent inhibition of apoptosis induced by genotoxic stress. Our results shed new light on the regulation of SIRT1 and have important implications in understanding the molecular mechanism of ageing and cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Ja-Eun -- Chen, Junjie -- Lou, Zhenkun -- England -- Nature. 2008 Jan 31;451(7178):583-6. doi: 10.1038/nature06500.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18235501" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/genetics/*metabolism ; Aging ; Apoptosis/drug effects ; Catalytic Domain ; Cell Line ; Down-Regulation ; Etoposide/pharmacology ; Humans ; Immunoprecipitation ; Leucine Zippers ; Mutagens/pharmacology ; Protein Binding ; Protein Interaction Mapping ; Sirtuin 1 ; Sirtuins/*antagonists & inhibitors/chemistry/genetics/*metabolism
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    UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-02-29
    Description: Signalling by means of toll-like receptors (TLRs) is essential for the development of innate and adaptive immune responses. UNC93B1, essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER). Here we show that the function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes. In dendritic cells of 3d mice, which express an UNC93B1 missense mutant (H412R) incapable of TLR binding, neither TLR7 nor TLR9 exits the ER. Furthermore, the trafficking and signalling defects of the nucleotide-sensing TLRs in 3d dendritic cells are corrected by expression of wild-type UNC93B1. However, UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs. To our knowledge, UNC93B1 is the first protein to be identified as a molecule specifically involved in trafficking of nucleotide-sensing TLRs. By inhibiting the interaction between UNC93B1 and TLRs it should be possible to achieve specific regulation of the nucleotide-sensing TLRs without compromising signalling via the cell-surface-disposed TLRs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, You-Me -- Brinkmann, Melanie M -- Paquet, Marie-Eve -- Ploegh, Hidde L -- England -- Nature. 2008 Mar 13;452(7184):234-8. doi: 10.1038/nature06726. Epub 2008 Feb 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. ykim@wi.mit.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18305481" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Dendritic Cells/metabolism ; *Endocytosis ; Endoplasmic Reticulum/metabolism ; Humans ; Ligands ; Lysosomes/*metabolism ; Membrane Glycoproteins/*metabolism ; Membrane Transport Proteins/chemistry/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mutation ; Nucleotides/*metabolism ; Protein Transport ; Signal Transduction ; Toll-Like Receptor 7/*metabolism ; Toll-Like Receptor 9/*metabolism
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    TRPC channel activation by extracellular thioredoxin (2008)
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    Publication Date: 2008-01-04
    Description: Mammalian homologues of Drosophila melanogaster transient receptor potential (TRP) are a large family of multimeric cation channels that act, or putatively act, as sensors of one or more chemical factor. Major research objectives are the identification of endogenous activators and the determination of cellular and tissue functions of these channels. Here we show the activation of TRPC5 (canonical TRP 5) homomultimeric and TRPC5-TRPC1 heteromultimeric channels by extracellular reduced thioredoxin, which acts by breaking a disulphide bridge in the predicted extracellular loop adjacent to the ion-selectivity filter of TRPC5. Thioredoxin is an endogenous redox protein with established intracellular functions, but it is also secreted and its extracellular targets are largely unknown. Particularly high extracellular concentrations of thioredoxin are apparent in rheumatoid arthritis, an inflammatory joint disease that disables millions of people worldwide. We show that TRPC5 and TRPC1 are expressed in secretory fibroblast-like synoviocytes from patients with rheumatoid arthritis, that endogenous TRPC5-TRPC1 channels of the cells are activated by reduced thioredoxin, and that blockade of the channels enhances secretory activity and prevents the suppression of secretion by thioredoxin. The data indicate the presence of a previously unrecognized ion-channel activation mechanism that couples extracellular thioredoxin to cell function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645077/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645077/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Shang-Zhong -- Sukumar, Piruthivi -- Zeng, Fanning -- Li, Jing -- Jairaman, Amit -- English, Anne -- Naylor, Jacqueline -- Ciurtin, Coziana -- Majeed, Yasser -- Milligan, Carol J -- Bahnasi, Yahya M -- Al-Shawaf, Eman -- Porter, Karen E -- Jiang, Lin-Hua -- Emery, Paul -- Sivaprasadarao, Asipu -- Beech, David J -- 077424/Wellcome Trust/United Kingdom -- 083857/Wellcome Trust/United Kingdom -- 18475/Arthritis Research UK/United Kingdom -- BB/D524875/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2008 Jan 3;451(7174):69-72. doi: 10.1038/nature06414.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Membrane and Systems Biology, Garstang Building, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18172497" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arthritis, Rheumatoid/metabolism/pathology ; Cell Line ; Disulfides/chemistry/metabolism ; Electric Conductivity ; Humans ; Oxidation-Reduction/drug effects ; Patch-Clamp Techniques ; Rabbits ; TRPC Cation Channels/*agonists/chemistry/*metabolism ; Thioredoxins/chemistry/*pharmacology
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    Control of chromosome stability by the beta-TrCP-REST-Mad2 axis (2008)
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    Publication Date: 2008-03-21
    Description: REST/NRSF (repressor-element-1-silencing transcription factor/neuron-restrictive silencing factor) negatively regulates the transcription of genes containing RE1 sites. REST is expressed in non-neuronal cells and stem/progenitor neuronal cells, in which it inhibits the expression of neuron-specific genes. Overexpression of REST is frequently found in human medulloblastomas and neuroblastomas, in which it is thought to maintain the stem character of tumour cells. Neural stem cells forced to express REST and c-Myc fail to differentiate and give rise to tumours in the mouse cerebellum. Expression of a splice variant of REST that lacks the carboxy terminus has been associated with neuronal tumours and small-cell lung carcinomas, and a frameshift mutant (REST-FS), which is also truncated at the C terminus, has oncogenic properties. Here we show, by using an unbiased screen, that REST is an interactor of the F-box protein beta-TrCP. REST is degraded by means of the ubiquitin ligase SCF(beta-TrCP) during the G2 phase of the cell cycle to allow transcriptional derepression of Mad2, an essential component of the spindle assembly checkpoint. The expression in cultured cells of a stable REST mutant, which is unable to bind beta-TrCP, inhibited Mad2 expression and resulted in a phenotype analogous to that observed in Mad2(+/-) cells. In particular, we observed defects that were consistent with faulty activation of the spindle checkpoint, such as shortened mitosis, premature sister-chromatid separation, chromosome bridges and mis-segregation in anaphase, tetraploidy, and faster mitotic slippage in the presence of a spindle inhibitor. An indistinguishable phenotype was observed by expressing the oncogenic REST-FS mutant, which does not bind beta-TrCP. Thus, SCF(beta-TrCP)-dependent degradation of REST during G2 permits the optimal activation of the spindle checkpoint, and consequently it is required for the fidelity of mitosis. The high levels of REST or its truncated variants found in certain human tumours may contribute to cellular transformation by promoting genomic instability.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707768/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707768/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guardavaccaro, Daniele -- Frescas, David -- Dorrello, N Valerio -- Peschiaroli, Angelo -- Multani, Asha S -- Cardozo, Timothy -- Lasorella, Anna -- Iavarone, Antonio -- Chang, Sandy -- Hernando, Eva -- Pagano, Michele -- R01 GM057587/GM/NIGMS NIH HHS/ -- R01 GM057587-10/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 20;452(7185):365-9. doi: 10.1038/nature06641.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18354482" target="_blank"〉PubMed〈/a〉
    Keywords: Calcium-Binding Proteins/genetics/*metabolism ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line ; *Chromosomal Instability ; G2 Phase ; Gene Expression Regulation ; Genomic Instability ; Humans ; Mad2 Proteins ; Mitosis ; Protein Binding ; Repressor Proteins/genetics/*metabolism ; SKP Cullin F-Box Protein Ligases/metabolism ; Spindle Apparatus/physiology ; Transcription Factors/genetics/*metabolism ; beta-Transducin Repeat-Containing Proteins/deficiency/genetics/*metabolism
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    A PtdIns4,5P2-regulated nuclear poly(A) polymerase controls expression of select mRNAs (2008)
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    Publication Date: 2008-02-22
    Description: Phosphoinositides are a family of lipid signalling molecules that regulate many cellular functions in eukaryotes. Phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2), the central component in the phosphoinositide signalling circuitry, is generated primarily by type I phosphatidylinositol 4-phosphate 5-kinases (PIPKIalpha, PIPKIbeta and PIPKIgamma). In addition to functions in the cytosol, phosphoinositides are present in the nucleus, where they modulate several functions; however, the mechanism by which they directly regulate nuclear functions remains unknown. PIPKIs regulate cellular functions through interactions with protein partners, often PtdIns4,5P2 effectors, that target PIPKIs to discrete subcellular compartments, resulting in the spatial and temporal generation of PtdIns4,5P2 required for the regulation of specific signalling pathways. Therefore, to determine roles for nuclear PtdIns4,5P2 we set out to identify proteins that interacted with the nuclear PIPK, PIPKIalpha. Here we show that PIPKIalpha co-localizes at nuclear speckles and interacts with a newly identified non-canonical poly(A) polymerase, which we have termed Star-PAP (nuclear speckle targeted PIPKIalpha regulated-poly(A) polymerase) and that the activity of Star-PAP can be specifically regulated by PtdIns4,5P2. Star-PAP and PIPKIalpha function together in a complex to control the expression of select mRNAs, including the transcript encoding the key cytoprotective enzyme haem oxygenase-1 (refs 8, 9) and other oxidative stress response genes by regulating the 3'-end formation of their mRNAs. Taken together, the data demonstrate a model by which phosphoinositide signalling works in tandem with complement pathways to regulate the activity of Star-PAP and the subsequent biosynthesis of its target mRNA. The results reveal a mechanism for the integration of nuclear phosphoinositide signals and a method for regulating gene expression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mellman, David L -- Gonzales, Michael L -- Song, Chunhua -- Barlow, Christy A -- Wang, Ping -- Kendziorski, Christina -- Anderson, Richard A -- R01 GM051968/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Feb 21;451(7181):1013-7. doi: 10.1038/nature06666.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Molecular and Cellular Pharmacology, University of Wisconsin Medical School, University of Wisconsin-Madison, 1300 University Avenue, Madison, Wisconsin 53706, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18288197" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Nucleus/enzymology/genetics/*metabolism ; Heme Oxygenase-1/genetics ; Humans ; Mice ; Multiprotein Complexes/metabolism ; Oxidative Stress/genetics ; Phosphatidylinositol 4,5-Diphosphate ; Phosphatidylinositol Phosphates/*metabolism ; Phosphotransferases (Alcohol Group Acceptor)/deficiency/genetics/metabolism ; Polynucleotide Adenylyltransferase/chemistry/deficiency/genetics/*metabolism ; Protein Binding ; *RNA 3' End Processing ; RNA, Messenger/genetics/metabolism ; Substrate Specificity ; Transcription, Genetic
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    Haematopoietic stem cell release is regulated by circadian oscillations (2008)
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    Publication Date: 2008-02-08
    Description: Haematopoietic stem cells (HSCs) circulate in the bloodstream under steady-state conditions, but the mechanisms controlling their physiological trafficking are unknown. Here we show that circulating HSCs and their progenitors exhibit robust circadian fluctuations, peaking 5 h after the initiation of light and reaching a nadir 5 h after darkness. Circadian oscillations are markedly altered when mice are subjected to continuous light or to a 'jet lag' (defined as a shift of 12 h). Circulating HSCs and their progenitors fluctuate in antiphase with the expression of the chemokine CXCL12 in the bone marrow microenvironment. The cyclical release of HSCs and expression of Cxcl12 are regulated by core genes of the molecular clock through circadian noradrenaline secretion by the sympathetic nervous system. These adrenergic signals are locally delivered by nerves in the bone marrow, transmitted to stromal cells by the beta(3)-adrenergic receptor, leading to a decreased nuclear content of Sp1 transcription factor and the rapid downregulation of Cxcl12. These data indicate that a circadian, neurally driven release of HSC during the animal's resting period may promote the regeneration of the stem cell niche and possibly other tissues.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mendez-Ferrer, Simon -- Lucas, Daniel -- Battista, Michela -- Frenette, Paul S -- England -- Nature. 2008 Mar 27;452(7186):442-7. doi: 10.1038/nature06685. Epub 2008 Feb 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Mount Sinai School of Medicine, Department of Medicine and Department of Gene and Cell Medicine, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18256599" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Clocks/genetics/physiology/radiation effects ; Bone Marrow/*innervation/metabolism/radiation effects ; Bone Marrow Cells/metabolism/radiation effects ; Cell Line ; Chemokine CXCL12/genetics/metabolism ; Circadian Rhythm/*physiology/radiation effects ; Cues ; Gene Expression Regulation ; Hematopoietic Stem Cells/*cytology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Osteoblasts ; Photic Stimulation ; Receptors, Adrenergic, beta-3/deficiency/genetics/metabolism ; Sp1 Transcription Factor/metabolism ; Stromal Cells/metabolism ; Sympathetic Nervous System/metabolism/radiation effects
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    Domain organization of human chromosomes revealed by mapping of nuclear lamina interactions (2008)
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    Publication Date: 2008-05-09
    Description: The architecture of human chromosomes in interphase nuclei is still largely unknown. Microscopy studies have indicated that specific regions of chromosomes are located in close proximity to the nuclear lamina (NL). This has led to the idea that certain genomic elements may be attached to the NL, which may contribute to the spatial organization of chromosomes inside the nucleus. However, sequences in the human genome that interact with the NL in vivo have not been identified. Here we construct a high-resolution map of the interaction sites of the entire genome with NL components in human fibroblasts. This map shows that genome-lamina interactions occur through more than 1,300 sharply defined large domains 0.1-10 megabases in size. These lamina-associated domains (LADs) are typified by low gene-expression levels, indicating that LADs represent a repressive chromatin environment. The borders of LADs are demarcated by the insulator protein CTCF, by promoters that are oriented away from LADs, or by CpG islands, suggesting possible mechanisms of LAD confinement. Taken together, these results demonstrate that the human genome is divided into large, discrete domains that are units of chromosome organization within the nucleus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guelen, Lars -- Pagie, Ludo -- Brasset, Emilie -- Meuleman, Wouter -- Faza, Marius B -- Talhout, Wendy -- Eussen, Bert H -- de Klein, Annelies -- Wessels, Lodewyk -- de Laat, Wouter -- van Steensel, Bas -- England -- Nature. 2008 Jun 12;453(7197):948-51. doi: 10.1038/nature06947. Epub 2008 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Biology, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18463634" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Chromatin/genetics/metabolism ; *Chromosome Positioning ; Chromosomes, Human/genetics/*metabolism ; CpG Islands/genetics ; DNA-Binding Proteins/metabolism ; Fibroblasts ; Genome, Human ; Humans ; Lamin Type B/metabolism ; Nuclear Lamina/chemistry/*metabolism ; Promoter Regions, Genetic/genetics ; Protein Binding ; Repressor Proteins/metabolism
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    Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina (2008)
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    Publication Date: 2008-01-25
    Description: Synaptic circuits in the retina transform visual input gathered by photoreceptors into messages that retinal ganglion cells (RGCs) send to the brain. Processes of retinal interneurons (amacrine and bipolar cells) form synapses on dendrites of RGCs in the inner plexiform layer (IPL). The IPL is divided into at least 10 parallel sublaminae; subsets of interneurons and RGCs arborize and form synapses in just one or a few of them. These lamina-specific circuits determine the visual features to which RGC subtypes respond. Here we show that four closely related immunoglobulin superfamily (IgSF) adhesion molecules--Dscam (Down's syndrome cell adhesion molecule), DscamL (refs 6-9), Sidekick-1 and Sidekick-2 (ref. 10)--are expressed in chick by non-overlapping subsets of interneurons and RGCs that form synapses in distinct IPL sublaminae. Moreover, each protein is concentrated within the appropriate sublaminae and each mediates homophilic adhesion. Loss- and gain-of-function studies in vivo indicate that these IgSF members participate in determining the IPL sublaminae in which synaptic partners arborize and connect. Thus, vertebrate Dscams, like Drosophila Dscams, play roles in neural connectivity. Together, our results on Dscams and Sidekicks suggest the existence of an IgSF code for laminar specificity in retina and, by implication, in other parts of the central nervous system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yamagata, Masahito -- Sanes, Joshua R -- England -- Nature. 2008 Jan 24;451(7177):465-9. doi: 10.1038/nature06469.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology and Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18216854" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Adhesion ; Cell Line ; Chick Embryo ; Eye Proteins/genetics/*metabolism ; Gene Expression Profiling ; Humans ; Immunoglobulins/*chemistry ; Interneurons/metabolism ; Membrane Proteins/deficiency/genetics/*metabolism ; Neural Cell Adhesion Molecules/deficiency/genetics/*metabolism ; Organ Specificity ; Retina/*cytology/*metabolism ; Synapses/*metabolism
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    Cyclical DNA methylation of a transcriptionally active promoter (2008)
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    Publication Date: 2008-03-07
    Description: Processes that regulate gene transcription are directly under the influence of the genome organization. The epigenome contains additional information that is not brought by DNA sequence, and generates spatial and functional constraints that complement genetic instructions. DNA methylation on CpGs constitutes an epigenetic mark generally correlated with transcriptionally silent condensed chromatin. Replication of methylation patterns by DNA methyltransferases maintains genome stability through cell division. Here we present evidence of an unanticipated dynamic role for DNA methylation in gene regulation in human cells. Periodic, strand-specific methylation/demethylation occurs during transcriptional cycling of the pS2/TFF1 gene promoter on activation by oestrogens. DNA methyltransferases exhibit dual actions during these cycles, being involved in CpG methylation and active demethylation of 5mCpGs through deamination. Inhibition of this process precludes demethylation of the pS2 gene promoter and its subsequent transcriptional activation. Cyclical changes in the methylation status of promoter CpGs may thus represent a critical event in transcriptional achievement.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metivier, Raphael -- Gallais, Rozenn -- Tiffoche, Christophe -- Le Peron, Christine -- Jurkowska, Renata Z -- Carmouche, Richard P -- Ibberson, David -- Barath, Peter -- Demay, Florence -- Reid, George -- Benes, Vladimir -- Jeltsch, Albert -- Gannon, Frank -- Salbert, Gilles -- England -- Nature. 2008 Mar 6;452(7183):45-50. doi: 10.1038/nature06544.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite de Rennes I, CNRS, UMR 6026 Equipe SPARTE, IFR 140 GFAS, Campus de Beaulieu, 35042 Rennes cedex, France. Raphael.Metivier@univ-rennes1.fr〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18322525" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Chromatin Immunoprecipitation ; CpG Islands/genetics ; DNA (Cytosine-5-)-Methyltransferase/antagonists & inhibitors/metabolism ; *DNA Methylation/drug effects ; DNA Repair ; Deamination ; Estrogens/pharmacology ; *Gene Expression Regulation/drug effects ; Humans ; Kinetics ; Promoter Regions, Genetic/*genetics ; Thymine DNA Glycosylase/metabolism ; Transcription, Genetic/drug effects/*genetics ; Transcriptional Activation/drug effects/*genetics ; Tumor Suppressor Proteins/*genetics
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    Functional genomic screen reveals genes involved in lipid-droplet formation and utilization (2008)
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    Publication Date: 2008-04-15
    Description: Eukaryotic cells store neutral lipids in cytoplasmic lipid droplets enclosed in a monolayer of phospholipids and associated proteins. These dynamic organelles serve as the principal reservoirs for storing cellular energy and for the building blocks for membrane lipids. Excessive lipid accumulation in cells is a central feature of obesity, diabetes and atherosclerosis, yet remarkably little is known about lipid-droplet cell biology. Here we show, by means of a genome-wide RNA interference (RNAi) screen in Drosophila S2 cells that about 1.5% of all genes function in lipid-droplet formation and regulation. The phenotypes of the gene knockdowns sorted into five distinct phenotypic classes. Genes encoding enzymes of phospholipid biosynthesis proved to be determinants of lipid-droplet size and number, suggesting that the phospholipid composition of the monolayer profoundly affects droplet morphology and lipid utilization. A subset of the Arf1-COPI vesicular transport proteins also regulated droplet morphology and lipid utilization, thereby identifying a previously unrecognized function for this machinery. These phenotypes are conserved in mammalian cells, suggesting that insights from these studies are likely to be central to our understanding of human diseases involving excessive lipid storage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734507/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2734507/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Yi -- Walther, Tobias C -- Rao, Meghana -- Stuurman, Nico -- Goshima, Gohta -- Terayama, Koji -- Wong, Jinny S -- Vale, Ronald D -- Walter, Peter -- Farese, Robert V -- R21 DK078254/DK/NIDDK NIH HHS/ -- R21 DK078254-01/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 May 29;453(7195):657-61. doi: 10.1038/nature06928. Epub 2008 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18408709" target="_blank"〉PubMed〈/a〉
    Keywords: ADP-Ribosylation Factors/metabolism ; Animals ; Cell Line ; Coat Protein Complex I/metabolism ; Drosophila Proteins/*genetics ; Drosophila melanogaster/*cytology/*genetics ; Genes, Insect/*genetics ; Genome, Insect/*genetics ; *Genomics ; Lipid Metabolism/*genetics ; Lipolysis ; Phenotype ; Phosphatidylcholines/metabolism ; RNA Interference
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    SMAD proteins control DROSHA-mediated microRNA maturation (2008)
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    Publication Date: 2008-06-13
    Description: MicroRNAs (miRNAs) are small non-coding RNAs that participate in the spatiotemporal regulation of messenger RNA and protein synthesis. Aberrant miRNA expression leads to developmental abnormalities and diseases, such as cardiovascular disorders and cancer; however, the stimuli and processes regulating miRNA biogenesis are largely unknown. The transforming growth factor beta (TGF-beta) and bone morphogenetic protein (BMP) family of growth factors orchestrates fundamental biological processes in development and in the homeostasis of adult tissues, including the vasculature. Here we show that induction of a contractile phenotype in human vascular smooth muscle cells by TGF-beta and BMPs is mediated by miR-21. miR-21 downregulates PDCD4 (programmed cell death 4), which in turn acts as a negative regulator of smooth muscle contractile genes. Surprisingly, TGF-beta and BMP signalling promotes a rapid increase in expression of mature miR-21 through a post-transcriptional step, promoting the processing of primary transcripts of miR-21 (pri-miR-21) into precursor miR-21 (pre-miR-21) by the DROSHA (also known as RNASEN) complex. TGF-beta- and BMP-specific SMAD signal transducers are recruited to pri-miR-21 in a complex with the RNA helicase p68 (also known as DDX5), a component of the DROSHA microprocessor complex. The shared cofactor SMAD4 is not required for this process. Thus, regulation of miRNA biogenesis by ligand-specific SMAD proteins is critical for control of the vascular smooth muscle cell phenotype and potentially for SMAD4-independent responses mediated by the TGF-beta and BMP signalling pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653422/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653422/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davis, Brandi N -- Hilyard, Aaron C -- Lagna, Giorgio -- Hata, Akiko -- HD042149/HD/NICHD NIH HHS/ -- HL082854/HL/NHLBI NIH HHS/ -- HL086572/HL/NHLBI NIH HHS/ -- R01 HD042149/HD/NICHD NIH HHS/ -- R01 HD042149-05/HD/NICHD NIH HHS/ -- R01 HL082854/HL/NHLBI NIH HHS/ -- R01 HL082854-03/HL/NHLBI NIH HHS/ -- R21 HL086572/HL/NHLBI NIH HHS/ -- R21 HL086572-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2008 Jul 3;454(7200):56-61. doi: 10.1038/nature07086. Epub 2008 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18548003" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/metabolism ; Bone Morphogenetic Protein 4 ; Bone Morphogenetic Proteins/metabolism/pharmacology ; Breast Neoplasms/genetics ; Cell Line ; Cercopithecus aethiops ; DEAD-box RNA Helicases/metabolism ; Gene Expression Regulation/drug effects ; Humans ; Ligands ; Mice ; MicroRNAs/biosynthesis/*metabolism ; Muscle, Smooth/metabolism ; Phenotype ; Protein Binding ; *RNA Processing, Post-Transcriptional ; RNA-Binding Proteins/metabolism ; Ribonuclease III/*metabolism ; Signal Transduction/drug effects ; Smad Proteins/*metabolism ; Transforming Growth Factor beta/metabolism/pharmacology
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    DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes (2008)
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    Publication Date: 2008-10-14
    Description: DNA double-strand breaks are generated by genotoxic agents and by cellular endonucleases as intermediates of several important physiological processes. The cellular response to genotoxic DNA breaks includes the activation of transcriptional programs known primarily to regulate cell-cycle checkpoints and cell survival. DNA double-strand breaks are generated in all developing lymphocytes during the assembly of antigen receptor genes, a process that is essential for normal lymphocyte development. Here we show that in murine lymphocytes these physiological DNA breaks activate a broad transcriptional program. This program transcends the canonical DNA double-strand break response and includes many genes that regulate diverse cellular processes important for lymphocyte development. Moreover, the expression of several of these genes is regulated similarly in response to genotoxic DNA damage. Thus, physiological DNA double-strand breaks provide cues that can regulate cell-type-specific processes not directly involved in maintaining the integrity of the genome, and genotoxic DNA breaks could disrupt normal cellular functions by corrupting these processes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605662/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605662/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bredemeyer, Andrea L -- Helmink, Beth A -- Innes, Cynthia L -- Calderon, Boris -- McGinnis, Lisa M -- Mahowald, Grace K -- Gapud, Eric J -- Walker, Laura M -- Collins, Jennifer B -- Weaver, Brian K -- Mandik-Nayak, Laura -- Schreiber, Robert D -- Allen, Paul M -- May, Michael J -- Paules, Richard S -- Bassing, Craig H -- Sleckman, Barry P -- R01 AI047829/AI/NIAID NIH HHS/ -- R01 AI047829-09/AI/NIAID NIH HHS/ -- R01 CA125195/CA/NCI NIH HHS/ -- R01 CA125195-02/CA/NCI NIH HHS/ -- England -- Nature. 2008 Dec 11;456(7223):819-23. doi: 10.1038/nature07392. Epub 2008 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18849970" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxia Telangiectasia Mutated Proteins ; B-Lymphocytes/drug effects/*metabolism ; Cell Cycle Proteins/drug effects ; Cell Line ; *DNA Breaks, Double-Stranded ; DNA-Binding Proteins/drug effects ; Enzyme Inhibitors/pharmacology ; Gene Expression Profiling ; Gene Expression Regulation, Developmental/drug effects/*genetics ; Homeodomain Proteins/metabolism ; Mice ; Mice, Knockout ; Mice, SCID ; NF-kappa B/metabolism ; Protein-Serine-Threonine Kinases/drug effects ; Tumor Suppressor Proteins/drug effects
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    IL-21 and TGF-beta are required for differentiation of human T(H)17 cells (2008)
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    Publication Date: 2008-05-13
    Description: The recent discovery of CD4(+) T cells characterized by secretion of interleukin (IL)-17 (T(H)17 cells) and the naturally occurring regulatory FOXP3(+) CD4 T cell (nT(reg)) has had a major impact on our understanding of immune processes not readily explained by the T(H)1/T(H)2 paradigm. T(H)17 and nT(reg) cells have been implicated in the pathogenesis of human autoimmune diseases, including multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis. Our recent data and the work of others demonstrated that transforming growth factor-beta (TGF-beta) and IL-6 are responsible for the differentiation of naive mouse T cells into T(H)17 cells, and it has been proposed that IL-23 may have a critical role in stabilization of the T(H)17 phenotype. A second pathway has been discovered in which a combination of TGF-beta and IL-21 is capable of inducing differentiation of mouse T(H)17 cells in the absence of IL-6 (refs 6-8). However, TGF-beta and IL-6 are not capable of differentiating human T(H)17 cells and it has been suggested that TGF-beta may in fact suppress the generation of human T(H)17 cells. Instead, it has been recently shown that the cytokines IL-1beta, IL-6 and IL-23 are capable of driving IL-17 secretion in short-term CD4(+) T cell lines isolated from human peripheral blood, although the factors required for differentiation of naive human CD4 to T(H)17 cells are still unknown. Here we confirm that whereas IL-1beta and IL-6 induce IL-17A secretion from human central memory CD4(+) T cells, TGF-beta and IL-21 uniquely promote the differentiation of human naive CD4(+) T cells into T(H)17 cells accompanied by expression of the transcription factor RORC2. These data will allow the investigation of this new population of T(H)17 cells in human inflammatory disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760130/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760130/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Li -- Anderson, David E -- Baecher-Allan, Clare -- Hastings, William D -- Bettelli, Estelle -- Oukka, Mohamed -- Kuchroo, Vijay K -- Hafler, David A -- P01 AI039671/AI/NIAID NIH HHS/ -- P01 AI039671-14/AI/NIAID NIH HHS/ -- P01 NS038037/NS/NINDS NIH HHS/ -- P01 NS038037-080006/NS/NINDS NIH HHS/ -- R01 AI073542/AI/NIAID NIH HHS/ -- R01 AI073542-01/AI/NIAID NIH HHS/ -- R01 AI073542-02/AI/NIAID NIH HHS/ -- R01 AI073542-03/AI/NIAID NIH HHS/ -- R37 NS024247/NS/NINDS NIH HHS/ -- R37 NS024247-20/NS/NINDS NIH HHS/ -- U19 AI070352/AI/NIAID NIH HHS/ -- U19 AI070352-03/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Jul 17;454(7202):350-2. doi: 10.1038/nature07021. Epub 2008 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Immunology, Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18469800" target="_blank"〉PubMed〈/a〉
    Keywords: *Cell Differentiation ; Cell Line ; Cells, Cultured ; Gene Expression Regulation ; Humans ; Interleukin-17/metabolism ; Interleukins/*metabolism ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; T-Lymphocytes, Helper-Inducer/*cytology/*metabolism ; Transcription Factors/genetics/metabolism ; Transforming Growth Factor beta1/*metabolism
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    Structural basis for EGFR ligand sequestration by Argos (2008)
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    Publication Date: 2008-05-27
    Description: Members of the epidermal growth factor receptor (EGFR) or ErbB/HER family and their activating ligands are essential regulators of diverse developmental processes. Inappropriate activation of these receptors is a key feature of many human cancers, and its reversal is an important clinical goal. A natural secreted antagonist of EGFR signalling, called Argos, was identified in Drosophila. We showed previously that Argos functions by directly binding (and sequestering) growth factor ligands that activate EGFR. Here we describe the 1.6-A resolution crystal structure of Argos bound to an EGFR ligand. Contrary to expectations, Argos contains no EGF-like domain. Instead, a trio of closely related domains (resembling a three-finger toxin fold) form a clamp-like structure around the bound EGF ligand. Although structurally unrelated to the receptor, Argos mimics EGFR by using a bipartite binding surface to entrap EGF. The individual Argos domains share unexpected structural similarities with the extracellular ligand-binding regions of transforming growth factor-beta family receptors. The three-domain clamp of Argos also resembles the urokinase-type plasminogen activator (uPA) receptor, which uses a similar mechanism to engulf the EGF-like module of uPA. Our results indicate that undiscovered mammalian counterparts of Argos may exist among other poorly characterized structural homologues. In addition, the structures presented here define requirements for the design of artificial EGF-sequestering proteins that would be valuable anti-cancer therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526102/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2526102/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klein, Daryl E -- Stayrook, Steven E -- Shi, Fumin -- Narayan, Kartik -- Lemmon, Mark A -- R01 CA079992/CA/NCI NIH HHS/ -- R01 CA079992-10/CA/NCI NIH HHS/ -- R01 CA125432/CA/NCI NIH HHS/ -- R01 CA125432-01A1/CA/NCI NIH HHS/ -- England -- Nature. 2008 Jun 26;453(7199):1271-5. doi: 10.1038/nature06978. Epub 2008 May 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, 809C Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, Pennsylvania 19104-6059, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18500331" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Cell Line ; Crystallography, X-Ray ; Drosophila Proteins/*chemistry/*metabolism ; Drosophila melanogaster/*chemistry/cytology ; Epidermal Growth Factor/*chemistry/*metabolism ; Eye Proteins/*chemistry/*metabolism ; Humans ; Ligands ; Membrane Proteins/*chemistry/*metabolism ; Models, Molecular ; Nerve Tissue Proteins/*chemistry/*metabolism ; Protein Structure, Tertiary ; Receptor, Epidermal Growth Factor/antagonists & inhibitors/chemistry/*metabolism ; Receptors, Transforming Growth Factor beta/chemistry/metabolism ; Spodoptera
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    Human cardiovascular progenitor cells develop from a KDR+ embryonic-stem-cell-derived population (2008)
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    Publication Date: 2008-04-25
    Description: The functional heart is comprised of distinct mesoderm-derived lineages including cardiomyocytes, endothelial cells and vascular smooth muscle cells. Studies in the mouse embryo and the mouse embryonic stem cell differentiation model have provided evidence indicating that these three lineages develop from a common Flk-1(+) (kinase insert domain protein receptor, also known as Kdr) cardiovascular progenitor that represents one of the earliest stages in mesoderm specification to the cardiovascular lineages. To determine whether a comparable progenitor is present during human cardiogenesis, we analysed the development of the cardiovascular lineages in human embryonic stem cell differentiation cultures. Here we show that after induction with combinations of activin A, bone morphogenetic protein 4 (BMP4), basic fibroblast growth factor (bFGF, also known as FGF2), vascular endothelial growth factor (VEGF, also known as VEGFA) and dickkopf homolog 1 (DKK1) in serum-free media, human embryonic-stem-cell-derived embryoid bodies generate a KDR(low)/C-KIT(CD117)(neg) population that displays cardiac, endothelial and vascular smooth muscle potential in vitro and, after transplantation, in vivo. When plated in monolayer cultures, these KDR(low)/C-KIT(neg) cells differentiate to generate populations consisting of greater than 50% contracting cardiomyocytes. Populations derived from the KDR(low)/C-KIT(neg) fraction give rise to colonies that contain all three lineages when plated in methylcellulose cultures. Results from limiting dilution studies and cell-mixing experiments support the interpretation that these colonies are clones, indicating that they develop from a cardiovascular colony-forming cell. Together, these findings identify a human cardiovascular progenitor that defines one of the earliest stages of human cardiac development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Lei -- Soonpaa, Mark H -- Adler, Eric D -- Roepke, Torsten K -- Kattman, Steven J -- Kennedy, Marion -- Henckaerts, Els -- Bonham, Kristina -- Abbott, Geoffrey W -- Linden, R Michael -- Field, Loren J -- Keller, Gordon M -- R01 HL079275/HL/NHLBI NIH HHS/ -- R01 HL083126/HL/NHLBI NIH HHS/ -- R01 HL083126-03/HL/NHLBI NIH HHS/ -- England -- Nature. 2008 May 22;453(7194):524-8. doi: 10.1038/nature06894. Epub 2008 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Gene and Cell Medicine, The Black Family Stem Cell Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18432194" target="_blank"〉PubMed〈/a〉
    Keywords: Activins/pharmacology ; Bone Morphogenetic Protein 4 ; Bone Morphogenetic Proteins/pharmacology ; Cell Differentiation/drug effects ; Cell Line ; Cell Lineage/drug effects ; Embryonic Stem Cells/*cytology/drug effects/*metabolism/transplantation ; Fibroblast Growth Factor 2/pharmacology ; Humans ; Intercellular Signaling Peptides and Proteins/pharmacology ; Myocytes, Cardiac/*cytology/drug effects/metabolism ; Patch-Clamp Techniques ; Proto-Oncogene Proteins c-kit/genetics ; Vascular Endothelial Growth Factor A/pharmacology ; Vascular Endothelial Growth Factor Receptor-2/deficiency/genetics/*metabolism
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    SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin (2008)
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    Publication Date: 2008-03-14
    Description: The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing-like phenotype. However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-associated protein, but no enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin. SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome. We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. Our findings constitute the first identification of a physiological enzymatic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646112/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646112/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Michishita, Eriko -- McCord, Ronald A -- Berber, Elisabeth -- Kioi, Mitomu -- Padilla-Nash, Hesed -- Damian, Mara -- Cheung, Peggie -- Kusumoto, Rika -- Kawahara, Tiara L A -- Barrett, J Carl -- Chang, Howard Y -- Bohr, Vilhelm A -- Ried, Thomas -- Gozani, Or -- Chua, Katrin F -- K08 AG028961/AG/NIA NIH HHS/ -- K08 AG028961-03/AG/NIA NIH HHS/ -- R01 AG028867/AG/NIA NIH HHS/ -- R01 AG028867-03/AG/NIA NIH HHS/ -- R01 GM079641/GM/NIGMS NIH HHS/ -- R01 GM079641-02/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Mar 27;452(7186):492-6. doi: 10.1038/nature06736. Epub 2008 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337721" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Cell Aging/genetics ; Cell Line ; Chromatin/genetics/*metabolism ; DNA Replication ; Exodeoxyribonucleases/metabolism ; Fibroblasts ; Histone Deacetylases/deficiency/genetics/*metabolism ; Histones/chemistry/metabolism ; Humans ; Lysine/metabolism ; Phenotype ; Protein Binding ; RecQ Helicases/metabolism ; Sirtuins/deficiency/genetics/*metabolism ; Telomerase/genetics/metabolism ; Telomere/genetics/*metabolism ; Werner Syndrome/genetics
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    Sequence- and target-independent angiogenesis suppression by siRNA via TLR3 (2008)
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    Publication Date: 2008-03-28
    Description: Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 (also called FLT1), in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration, are premised on gene silencing by means of intracellular RNA interference (RNAi). We show instead that CNV inhibition is a siRNA-class effect: 21-nucleotide or longer siRNAs targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro- and anti-angiogenic genes, and RNAi-incompetent siRNAs all suppressed CNV in mice comparably to siRNAs targeting Vegfa or Vegfr1 without off-target RNAi or interferon-alpha/beta activation. Non-targeted (against non-mammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell-surface toll-like receptor 3 (TLR3), its adaptor TRIF, and induction of interferon-gamma and interleukin-12. Non-targeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modelled 2:1 TLR3-RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642938/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642938/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kleinman, Mark E -- Yamada, Kiyoshi -- Takeda, Atsunobu -- Chandrasekaran, Vasu -- Nozaki, Miho -- Baffi, Judit Z -- Albuquerque, Romulo J C -- Yamasaki, Satoshi -- Itaya, Masahiro -- Pan, Yuzhen -- Appukuttan, Binoy -- Gibbs, Daniel -- Yang, Zhenglin -- Kariko, Katalin -- Ambati, Balamurali K -- Wilgus, Traci A -- DiPietro, Luisa A -- Sakurai, Eiji -- Zhang, Kang -- Smith, Justine R -- Taylor, Ethan W -- Ambati, Jayakrishna -- R01 EY015422/EY/NEI NIH HHS/ -- R01 EY015422-04/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018350-02/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY018836-01/EY/NEI NIH HHS/ -- England -- Nature. 2008 Apr 3;452(7187):591-7. doi: 10.1038/nature06765. Epub 2008 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology, University of Kentucky, Lexington, Kentucky 40506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18368052" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Endothelial Cells/metabolism ; Genetic Therapy/*methods ; Humans ; Immunity, Innate/*immunology ; Interferon-gamma/immunology ; Interleukin-12/immunology ; Macular Degeneration/complications/genetics/therapy ; Mice ; Mice, Inbred C57BL ; Neovascularization, Pathologic/genetics/*immunology/*prevention & control/therapy ; RNA, Small Interfering/chemistry/genetics/*immunology/*metabolism ; Toll-Like Receptor 3/chemistry/genetics/*metabolism ; Vascular Endothelial Growth Factor A/genetics
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    Dissecting direct reprogramming through integrative genomic analysis (2008)
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    Publication Date: 2008-05-30
    Description: Somatic cells can be reprogrammed to a pluripotent state through the ectopic expression of defined transcription factors. Understanding the mechanism and kinetics of this transformation may shed light on the nature of developmental potency and suggest strategies with improved efficiency or safety. Here we report an integrative genomic analysis of reprogramming of mouse fibroblasts and B lymphocytes. Lineage-committed cells show a complex response to the ectopic expression involving induction of genes downstream of individual reprogramming factors. Fully reprogrammed cells show gene expression and epigenetic states that are highly similar to embryonic stem cells. In contrast, stable partially reprogrammed cell lines show reactivation of a distinctive subset of stem-cell-related genes, incomplete repression of lineage-specifying transcription factors, and DNA hypermethylation at pluripotency-related loci. These observations suggest that some cells may become trapped in partially reprogrammed states owing to incomplete repression of transcription factors, and that DNA de-methylation is an inefficient step in the transition to pluripotency. We demonstrate that RNA inhibition of transcription factors can facilitate reprogramming, and that treatment with DNA methyltransferase inhibitors can improve the overall efficiency of the reprogramming process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754827/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754827/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mikkelsen, Tarjei S -- Hanna, Jacob -- Zhang, Xiaolan -- Ku, Manching -- Wernig, Marius -- Schorderet, Patrick -- Bernstein, Bradley E -- Jaenisch, Rudolf -- Lander, Eric S -- Meissner, Alexander -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-04/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Jul 3;454(7200):49-55. doi: 10.1038/nature07056. Epub 2008 May 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18509334" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Azacitidine/pharmacology ; Cell Line ; Cell Lineage ; Cellular Reprogramming/*genetics ; Chromatin/metabolism ; DNA (Cytosine-5-)-Methyltransferase/antagonists & inhibitors/genetics/metabolism ; DNA Methylation ; Embryonic Stem Cells/metabolism ; Enzyme Inhibitors/pharmacology ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Genome/genetics ; *Genomics ; Mice ; Pluripotent Stem Cells/cytology/*metabolism ; Transcription Factors/deficiency/genetics
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    MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation (2008)
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    Publication Date: 2008-09-23
    Description: MicroRNAs (miRNAs) are short RNAs that direct messenger RNA degradation or disrupt mRNA translation in a sequence-dependent manner. For more than a decade, attempts to study the interaction of miRNAs with their targets were confined to the 3' untranslated regions of mRNAs, fuelling an underlying assumption that these regions are the principal recipients of miRNA activity. Here we focus on the mouse Nanog, Oct4 (also known as Pou5f1) and Sox2 genes and demonstrate the existence of many naturally occurring miRNA targets in their amino acid coding sequence (CDS). Some of the mouse targets analysed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. miR-134, miR-296 and miR-470, upregulated on retinoic-acid-induced differentiation of mouse embryonic stem cells, target the CDS of each transcription factor in various combinations, leading to transcriptional and morphological changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolish miRNA activity, prevent the downregulation of the corresponding genes and delay the induced phenotype. Our findings demonstrate the abundance of CDS-located miRNA targets, some of which can be species-specific, and support an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3' untranslated region.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tay, Yvonne -- Zhang, Jinqiu -- Thomson, Andrew M -- Lim, Bing -- Rigoutsos, Isidore -- AI54973/AI/NIAID NIH HHS/ -- DK47636/DK/NIDDK NIH HHS/ -- England -- Nature. 2008 Oct 23;455(7216):1124-8. doi: 10.1038/nature07299. Epub 2008 Sep 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stem Cell and Developmental Biology, Genome Institute of Singapore, Agency for Science Technology and Research, #08-01, Genome, 60 Biopolis Street, Singapore 138672, Singapore.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18806776" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blotting, Western ; Cell Differentiation/*genetics ; Cell Line ; DNA-Binding Proteins/*genetics/metabolism ; Embryonic Stem Cells/*cytology/metabolism ; *Gene Expression Regulation, Developmental ; HMGB Proteins/*genetics/metabolism ; Homeodomain Proteins/*genetics/metabolism ; Mice ; MicroRNAs/*genetics/metabolism ; Mutation ; Octamer Transcription Factor-3/*genetics/metabolism ; Open Reading Frames/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; SOXB1 Transcription Factors ; Transcription Factors/*genetics/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    A paracrine requirement for hedgehog signalling in cancer (2008)
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    Publication Date: 2008-08-30
    Description: Ligand-dependent activation of the hedgehog (Hh) signalling pathway has been associated with tumorigenesis in a number of human tissues. Here we show that, although previous reports have described a cell-autonomous role for Hh signalling in these tumours, Hh ligands fail to activate signalling in tumour epithelial cells. In contrast, our data support ligand-dependent activation of the Hh pathway in the stromal microenvironment. Specific inhibition of Hh signalling using small molecule inhibitors, a neutralizing anti-Hh antibody or genetic deletion of smoothened (Smo) in the mouse stroma results in growth inhibition in xenograft tumour models. Taken together, these studies demonstrate a paracrine requirement for Hh ligand signalling in the tumorigenesis of Hh-expressing cancers and have important implications for the development of Hh pathway antagonists in cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yauch, Robert L -- Gould, Stephen E -- Scales, Suzie J -- Tang, Tracy -- Tian, Hua -- Ahn, Christina P -- Marshall, Derek -- Fu, Ling -- Januario, Thomas -- Kallop, Dara -- Nannini-Pepe, Michelle -- Kotkow, Karen -- Marsters, James C -- Rubin, Lee L -- de Sauvage, Frederic J -- England -- Nature. 2008 Sep 18;455(7211):406-10. doi: 10.1038/nature07275. Epub 2008 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18754008" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Hedgehog Proteins/*metabolism ; Humans ; Ligands ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Neoplasms/genetics/*metabolism ; Paracrine Communication/*physiology ; Receptors, G-Protein-Coupled/deficiency/genetics/metabolism ; Stromal Cells/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Stem-cell law goes to the polls (2008)
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    Publication Date: 2008-10-31
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yeager, Ashley -- England -- Nature. 2008 Oct 30;455(7217):1154-5. doi: 10.1038/4551154a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18971982" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line ; Embryo Research/economics/*legislation & jurisprudence ; *Embryonic Stem Cells/cytology ; *Federal Government ; Female ; Humans ; Michigan ; *State Government
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    Clathrin is a key regulator of basolateral polarity (2008)
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    Publication Date: 2008-04-11
    Description: Clathrin-coated vesicles are vehicles for intracellular trafficking in all nucleated cells, from yeasts to humans. Many studies have demonstrated their essential roles in endocytosis and cellular signalling processes at the plasma membrane. By contrast, very few of their non-endocytic trafficking roles are known, the best characterized being the transport of hydrolases from the Golgi complex to the lysosome. Here we show that clathrin is required for polarity of the basolateral plasma membrane proteins in the epithelial cell line MDCK. Clathrin knockdown depolarized most basolateral proteins, by interfering with their biosynthetic delivery and recycling, but did not affect the polarity of apical proteins. Quantitative live imaging showed that chronic and acute clathrin knockdown selectively slowed down the exit of basolateral proteins from the Golgi complex, and promoted their mis-sorting into apical carrier vesicles. Our results demonstrate a broad requirement for clathrin in basolateral protein trafficking in epithelial cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078870/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deborde, Sylvie -- Perret, Emilie -- Gravotta, Diego -- Deora, Ami -- Salvarezza, Susana -- Schreiner, Ryan -- Rodriguez-Boulan, Enrique -- R01 EY008538/EY/NEI NIH HHS/ -- R01 GM034107/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Apr 10;452(7188):719-23. doi: 10.1038/nature06828.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology, Dyson Vision Research Institute, LC-300, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18401403" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cathepsin D/metabolism ; Cell Line ; *Cell Polarity ; Clathrin/deficiency/genetics/*metabolism ; Clathrin Heavy Chains/genetics/metabolism ; Dogs ; Epithelial Cells/*cytology/metabolism ; Golgi Apparatus/metabolism ; Humans ; Inulin/metabolism ; Lysosomes/metabolism ; Protein Transport ; Receptors, LDL/metabolism ; Receptors, Transferrin/metabolism ; Tight Junctions/metabolism ; Time Factors ; trans-Golgi Network/metabolism
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    SATB1 reprogrammes gene expression to promote breast tumour growth and metastasis (2008)
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    Publication Date: 2008-03-14
    Description: Mechanisms underlying global changes in gene expression during tumour progression are poorly understood. SATB1 is a genome organizer that tethers multiple genomic loci and recruits chromatin-remodelling enzymes to regulate chromatin structure and gene expression. Here we show that SATB1 is expressed by aggressive breast cancer cells and its expression level has high prognostic significance (P 〈 0.0001), independent of lymph-node status. RNA-interference-mediated knockdown of SATB1 in highly aggressive (MDA-MB-231) cancer cells altered the expression of 〉1,000 genes, reversing tumorigenesis by restoring breast-like acinar polarity and inhibiting tumour growth and metastasis in vivo. Conversely, ectopic SATB1 expression in non-aggressive (SKBR3) cells led to gene expression patterns consistent with aggressive-tumour phenotypes, acquiring metastatic activity in vivo. SATB1 delineates specific epigenetic modifications at target gene loci, directly upregulating metastasis-associated genes while downregulating tumour-suppressor genes. SATB1 reprogrammes chromatin organization and the transcription profiles of breast tumours to promote growth and metastasis; this is a new mechanism of tumour progression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Han, Hye-Jung -- Russo, Jose -- Kohwi, Yoshinori -- Kohwi-Shigematsu, Terumi -- England -- Nature. 2008 Mar 13;452(7184):187-93. doi: 10.1038/nature06781.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337816" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomarkers, Tumor/analysis ; Breast Neoplasms/diagnosis/*genetics/*pathology ; Cell Line ; Cell Line, Tumor ; Cell Polarity ; Disease Progression ; Epigenesis, Genetic/genetics ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/*genetics ; Humans ; Lung Neoplasms/pathology/secretion ; Lymphatic Metastasis/diagnosis/genetics/pathology ; Matrix Attachment Region Binding Proteins/deficiency/genetics/*metabolism ; Mice ; Mice, Nude ; Neoplasm Metastasis/diagnosis/*genetics/pathology ; Neoplasm Transplantation ; Phenotype ; Prognosis ; RNA Interference
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    Neutralizing antibodies derived from the B cells of 1918 influenza pandemic survivors (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-22
    Description: Investigation of the human antibody response to influenza virus infection has been largely limited to serology, with relatively little analysis at the molecular level. The 1918 H1N1 influenza virus pandemic was the most severe of the modern era. Recent work has recovered the gene sequences of this unusual strain, so that the 1918 pandemic virus could be reconstituted to display its unique virulence phenotypes. However, little is known about adaptive immunity to this virus. We took advantage of the 1918 virus sequencing and the resultant production of recombinant 1918 haemagglutinin (HA) protein antigen to characterize at the clonal level neutralizing antibodies induced by natural exposure of survivors to the 1918 pandemic virus. Here we show that of the 32 individuals tested that were born in or before 1915, each showed seroreactivity with the 1918 virus, nearly 90 years after the pandemic. Seven of the eight donor samples tested had circulating B cells that secreted antibodies that bound the 1918 HA. We isolated B cells from subjects and generated five monoclonal antibodies that showed potent neutralizing activity against 1918 virus from three separate donors. These antibodies also cross-reacted with the genetically similar HA of a 1930 swine H1N1 influenza strain, but did not cross-react with HAs of more contemporary human influenza viruses. The antibody genes had an unusually high degree of somatic mutation. The antibodies bound to the 1918 HA protein with high affinity, had exceptional virus-neutralizing potency and protected mice from lethal infection. Isolation of viruses that escaped inhibition suggested that the antibodies recognize classical antigenic sites on the HA surface. Thus, these studies demonstrate that survivors of the 1918 influenza pandemic possess highly functional, virus-neutralizing antibodies to this uniquely virulent virus, and that humans can sustain circulating B memory cells to viruses for many decades after exposure-well into the tenth decade of life.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848880/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848880/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Xiaocong -- Tsibane, Tshidi -- McGraw, Patricia A -- House, Frances S -- Keefer, Christopher J -- Hicar, Mark D -- Tumpey, Terrence M -- Pappas, Claudia -- Perrone, Lucy A -- Martinez, Osvaldo -- Stevens, James -- Wilson, Ian A -- Aguilar, Patricia V -- Altschuler, Eric L -- Basler, Christopher F -- Crowe, James E Jr -- AI057158/AI/NIAID NIH HHS/ -- AI42266/AI/NIAID NIH HHS/ -- CA55896/CA/NCI NIH HHS/ -- P01 AI058113/AI/NIAID NIH HHS/ -- R01 AI048677/AI/NIAID NIH HHS/ -- R01 AI048677-04/AI/NIAID NIH HHS/ -- U19 AI057229/AI/NIAID NIH HHS/ -- U19 AI62623/AI/NIAID NIH HHS/ -- U54 AI057157/AI/NIAID NIH HHS/ -- U54 AI057157-019002/AI/NIAID NIH HHS/ -- U54 AI57158/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Sep 25;455(7212):532-6. doi: 10.1038/nature07231. Epub 2008 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18716625" target="_blank"〉PubMed〈/a〉
    Keywords: Aged, 80 and over ; Animals ; Antibodies, Monoclonal/genetics/immunology/isolation & purification ; Antibodies, Viral/genetics/*immunology/*isolation & purification ; B-Lymphocytes/*immunology ; Cell Line ; Cross Reactions/immunology ; *Disease Outbreaks/history ; Dogs ; Female ; History, 20th Century ; Humans ; Influenza A Virus, H1N1 Subtype/genetics/*immunology/physiology ; Influenza, Human/*immunology/virology ; Kinetics ; Mice ; Mice, Inbred BALB C ; Molecular Sequence Data ; Neutralization Tests ; *Survival
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    MicroRNA-21 contributes to myocardial disease by stimulating MAP kinase signalling in fibroblasts (2008)
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    Publication Date: 2008-12-02
    Description: MicroRNAs comprise a broad class of small non-coding RNAs that control expression of complementary target messenger RNAs. Dysregulation of microRNAs by several mechanisms has been described in various disease states including cardiac disease. Whereas previous studies of cardiac disease have focused on microRNAs that are primarily expressed in cardiomyocytes, the role of microRNAs expressed in other cell types of the heart is unclear. Here we show that microRNA-21 (miR-21, also known as Mirn21) regulates the ERK-MAP kinase signalling pathway in cardiac fibroblasts, which has impacts on global cardiac structure and function. miR-21 levels are increased selectively in fibroblasts of the failing heart, augmenting ERK-MAP kinase activity through inhibition of sprouty homologue 1 (Spry1). This mechanism regulates fibroblast survival and growth factor secretion, apparently controlling the extent of interstitial fibrosis and cardiac hypertrophy. In vivo silencing of miR-21 by a specific antagomir in a mouse pressure-overload-induced disease model reduces cardiac ERK-MAP kinase activity, inhibits interstitial fibrosis and attenuates cardiac dysfunction. These findings reveal that microRNAs can contribute to myocardial disease by an effect in cardiac fibroblasts. Our results validate miR-21 as a disease target in heart failure and establish the therapeutic efficacy of microRNA therapeutic intervention in a cardiovascular disease setting.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thum, Thomas -- Gross, Carina -- Fiedler, Jan -- Fischer, Thomas -- Kissler, Stephan -- Bussen, Markus -- Galuppo, Paolo -- Just, Steffen -- Rottbauer, Wolfgang -- Frantz, Stefan -- Castoldi, Mirco -- Soutschek, Jurgen -- Koteliansky, Victor -- Rosenwald, Andreas -- Basson, M Albert -- Licht, Jonathan D -- Pena, John T R -- Rouhanifard, Sara H -- Muckenthaler, Martina U -- Tuschl, Thomas -- Martin, Gail R -- Bauersachs, Johann -- Engelhardt, Stefan -- R01 CA059998/CA/NCI NIH HHS/ -- R01 CA78711/CA/NCI NIH HHS/ -- England -- Nature. 2008 Dec 18;456(7224):980-4. doi: 10.1038/nature07511. Epub 2008 Nov 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine I, Interdisziplinares Zentrum fur Klinische Forschung (IZKF), University of Wuerzburg, 97080 Wuerzburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19043405" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cardiomyopathies/*genetics/*metabolism/pathology/therapy ; Cell Line ; Cell Survival ; Cells, Cultured ; Disease Models, Animal ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fibroblasts/*metabolism ; Gene Silencing ; Humans ; *MAP Kinase Signaling System ; Male ; Mice ; Mice, Transgenic ; MicroRNAs/*genetics ; Myocytes, Cardiac/cytology/metabolism ; Rats
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    NLRX1 is a regulator of mitochondrial antiviral immunity (2008)
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    Publication Date: 2008-01-18
    Description: The RIG-like helicase (RLH) family of intracellular receptors detect viral nucleic acid and signal through the mitochondrial antiviral signalling adaptor MAVS (also known as Cardif, VISA and IPS-1) during a viral infection. MAVS activation leads to the rapid production of antiviral cytokines, including type 1 interferons. Although MAVS is vital to antiviral immunity, its regulation from within the mitochondria remains unknown. Here we describe human NLRX1, a highly conserved nucleotide-binding domain (NBD)- and leucine-rich-repeat (LRR)-containing family member (known as NLR) that localizes to the mitochondrial outer membrane and interacts with MAVS. Expression of NLRX1 results in the potent inhibition of RLH- and MAVS-mediated interferon-beta promoter activity and in the disruption of virus-induced RLH-MAVS interactions. Depletion of NLRX1 with small interference RNA promotes virus-induced type I interferon production and decreases viral replication. This work identifies NLRX1 as a check against mitochondrial antiviral responses and represents an intersection of three ancient cellular processes: NLR signalling, intracellular virus detection and the use of mitochondria as a platform for anti-pathogen signalling. This represents a conceptual advance, in that NLRX1 is a modulator of pathogen-associated molecular pattern receptors rather than a receptor, and identifies a key therapeutic target for enhancing antiviral responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moore, Chris B -- Bergstralh, Daniel T -- Duncan, Joseph A -- Lei, Yu -- Morrison, Thomas E -- Zimmermann, Albert G -- Accavitti-Loper, Mary A -- Madden, Victoria J -- Sun, Lijun -- Ye, Zhengmao -- Lich, John D -- Heise, Mark T -- Chen, Zhijian -- Ting, Jenny P-Y -- England -- Nature. 2008 Jan 31;451(7178):573-7. doi: 10.1038/nature06501. Epub 2008 Jan 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology-Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18200010" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/antagonists & inhibitors/metabolism ; Animals ; Cell Line ; Cloning, Molecular ; Computational Biology ; Humans ; Interferon-beta/biosynthesis/genetics/metabolism ; Mice ; Mitochondria/*immunology/*metabolism ; Mitochondrial Membranes/metabolism ; Mitochondrial Proteins/genetics/*metabolism ; NF-kappa B/metabolism ; Protein Binding ; Protein Transport ; RNA, Small Interfering/genetics/metabolism ; Signal Transduction ; Virus Replication ; Viruses/*immunology
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    E2F1 represses beta-catenin transcription and is antagonized by both pRB and CDK8 (2008)
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    Publication Date: 2008-09-17
    Description: The E2F1 transcription factor can promote proliferation or apoptosis when activated, and is a key downstream target of the retinoblastoma tumour suppressor protein (pRB). Here we show that E2F1 is a potent and specific inhibitor of beta-catenin/T-cell factor (TCF)-dependent transcription, and that this function contributes to E2F1-induced apoptosis. E2F1 deregulation suppresses beta-catenin activity in an adenomatous polyposis coli (APC)/glycogen synthase kinase-3 (GSK3)-independent manner, reducing the expression of key beta-catenin targets including c-MYC. This interaction explains why colorectal tumours, which depend on beta-catenin transcription for their abnormal proliferation, keep RB1 intact. Remarkably, E2F1 activity is also repressed by cyclin-dependent kinase-8 (CDK8), a colorectal oncoprotein. Elevated levels of CDK8 protect beta-catenin/TCF-dependent transcription from inhibition by E2F1. Thus, by retaining RB1 and amplifying CDK8, colorectal tumour cells select conditions that collectively suppress E2F1 and enhance the activity of beta-catenin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148807/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148807/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morris, Erick J -- Ji, Jun-Yuan -- Yang, Fajun -- Di Stefano, Luisa -- Herr, Anabel -- Moon, Nam-Sung -- Kwon, Eun-Jeong -- Haigis, Kevin M -- Naar, Anders M -- Dyson, Nicholas J -- GM053203/GM/NIGMS NIH HHS/ -- GM071449/GM/NIGMS NIH HHS/ -- GM81607/GM/NIGMS NIH HHS/ -- P50 CA127003/CA/NCI NIH HHS/ -- P50 CA127003-02/CA/NCI NIH HHS/ -- P50-CA127003/CA/NCI NIH HHS/ -- R01 GM053203/GM/NIGMS NIH HHS/ -- R01 GM053203-13/GM/NIGMS NIH HHS/ -- R01 GM053203-14/GM/NIGMS NIH HHS/ -- R01 GM071449/GM/NIGMS NIH HHS/ -- R01 GM071449-04/GM/NIGMS NIH HHS/ -- R01 GM081607/GM/NIGMS NIH HHS/ -- R01 GM081607-01A1/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Sep 25;455(7212):552-6. doi: 10.1038/nature07310. Epub 2008 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 13th Street, Building 149, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18794899" target="_blank"〉PubMed〈/a〉
    Keywords: Adenomatous Polyposis Coli Protein/metabolism ; Apoptosis ; Cell Line ; Cyclin-Dependent Kinase 8 ; Cyclin-Dependent Kinases/*metabolism ; E2F1 Transcription Factor/*antagonists & inhibitors/*metabolism ; Gene Expression Regulation ; Genes, myc/genetics ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Retinoblastoma Protein/genetics/*metabolism ; Signal Transduction ; TCF Transcription Factors/metabolism ; *Transcription, Genetic ; Wnt Proteins/metabolism ; beta Catenin/*antagonists & inhibitors/*metabolism
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    A modular switch for spatial Ca2+ selectivity in the calmodulin regulation of CaV channels (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-02-01
    Description: Ca2+/calmodulin-dependent regulation of voltage-gated CaV1-2 Ca2+ channels shows extraordinary modes of spatial Ca2+ decoding and channel modulation, vital for many biological functions. A single calmodulin (CaM) molecule associates constitutively with the channel's carboxy-terminal tail, and Ca2+ binding to the C-terminal and N-terminal lobes of CaM can each induce distinct channel regulations. As expected from close channel proximity, the C-lobe responds to the roughly 100-microM Ca2+ pulses driven by the associated channel, a behaviour defined as 'local Ca2+ selectivity'. Conversely, all previous observations have indicated that the N-lobe somehow senses the far weaker signals from distant Ca2+ sources. This 'global Ca2+ selectivity' satisfies a general signalling requirement, enabling a resident molecule to remotely sense cellular Ca2+ activity, which would otherwise be overshadowed by Ca2+ entry through the host channel. Here we show that the spatial Ca2+ selectivity of N-lobe CaM regulation is not invariably global but can be switched by a novel Ca2+/CaM-binding site within the amino terminus of channels (NSCaTE, for N-terminal spatial Ca2+ transforming element). Native CaV2.2 channels lack this element and show N-lobe regulation with a global selectivity. On the introduction of NSCaTE into these channels, spatial Ca2+ selectivity transforms from a global to local profile. Given this effect, we examined CaV1.2/CaV1.3 channels, which naturally contain NSCaTE, and found that their N-lobe selectivity is indeed local. Disruption of this element produces a global selectivity, confirming the native function of NSCaTE. Thus, differences in spatial selectivity between advanced CaV1 and CaV2 channel isoforms are explained by the presence or absence of NSCaTE. Beyond functional effects, the position of NSCaTE on the channel's amino terminus indicates that CaM can bridge the amino terminus and carboxy terminus of channels. Finally, the modularity of NSCaTE offers practical means for understanding the basis of global Ca2+ selectivity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262256/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262256/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dick, Ivy E -- Tadross, Michael R -- Liang, Haoya -- Tay, Lai Hock -- Yang, Wanjun -- Yue, David T -- P30 DC005211/DC/NIDCD NIH HHS/ -- R01 MH065531/MH/NIMH NIH HHS/ -- R37 HL076795/HL/NHLBI NIH HHS/ -- T32 DC000023/DC/NIDCD NIH HHS/ -- England -- Nature. 2008 Feb 14;451(7180):830-4. doi: 10.1038/nature06529. Epub 2008 Jan 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18235447" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Calcium/*metabolism ; Calcium Channels/chemistry/genetics/*metabolism ; *Calcium Signaling ; Calmodulin/*metabolism ; Cell Line ; Evolution, Molecular ; Humans ; Molecular Sequence Data ; Substrate Specificity
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    TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-03-28
    Description: T helper cells that produce IL-17 (T(H)17 cells) promote autoimmunity in mice and have been implicated in the pathogenesis of human inflammatory diseases. At mucosal surfaces, T(H)17 cells are thought to protect the host from infection, whereas regulatory T (T(reg)) cells control immune responses and inflammation triggered by the resident microflora. Differentiation of both cell types requires transforming growth factor-beta (TGF-beta), but depends on distinct transcription factors: RORgammat (encoded by Rorc(gammat)) for T(H)17 cells and Foxp3 for T(reg) cells. How TGF-beta regulates the differentiation of T cells with opposing activities has been perplexing. Here we demonstrate that, together with pro-inflammatory cytokines, TGF-beta orchestrates T(H)17 cell differentiation in a concentration-dependent manner. At low concentrations, TGF-beta synergizes with interleukin (IL)-6 and IL-21 (refs 9-11) to promote IL-23 receptor (Il23r) expression, favouring T(H)17 cell differentiation. High concentrations of TGF-beta repress IL23r expression and favour Foxp3+ T(reg) cells. RORgammat and Foxp3 are co-expressed in naive CD4+ T cells exposed to TGF-beta and in a subset of T cells in the small intestinal lamina propria of the mouse. In vitro, TGF-beta-induced Foxp3 inhibits RORgammat function, at least in part through their interaction. Accordingly, lamina propria T cells that co-express both transcription factors produce less IL-17 (also known as IL-17a) than those that express RORgammat alone. IL-6, IL-21 and IL-23 relieve Foxp3-mediated inhibition of RORgammat, thereby promoting T(H)17 cell differentiation. Therefore, the decision of antigen-stimulated cells to differentiate into either T(H)17 or T(reg) cells depends on the cytokine-regulated balance of RORgammat and Foxp3.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597437/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Liang -- Lopes, Jared E -- Chong, Mark M W -- Ivanov, Ivaylo I -- Min, Roy -- Victora, Gabriel D -- Shen, Yuelei -- Du, Jianguang -- Rubtsov, Yuri P -- Rudensky, Alexander Y -- Ziegler, Steven F -- Littman, Dan R -- AI48779/AI/NIAID NIH HHS/ -- R01 AI048779/AI/NIAID NIH HHS/ -- R01 AI048779-05/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 May 8;453(7192):236-40. doi: 10.1038/nature06878. Epub 2008 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18368049" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation/drug effects ; Cell Line ; Cells, Cultured ; Forkhead Transcription Factors/genetics/*metabolism ; Gene Expression Regulation/drug effects ; Humans ; Interleukin-17/biosynthesis/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Nuclear Receptor Subfamily 1, Group F, Member 3 ; Receptors, Interleukin/genetics/metabolism ; Receptors, Retinoic Acid/*antagonists & inhibitors/genetics/metabolism ; Receptors, Thyroid Hormone/*antagonists & inhibitors/genetics/metabolism ; T-Lymphocytes, Helper-Inducer/*cytology/*drug effects/metabolism ; Transforming Growth Factor beta/*pharmacology
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    Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA (2008)
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    Publication Date: 2008-06-13
    Description: Innate immune defences are essential for the control of virus infection and are triggered through host recognition of viral macromolecular motifs known as pathogen-associated molecular patterns (PAMPs). Hepatitis C virus (HCV) is an RNA virus that replicates in the liver, and infects 200 million people worldwide. Infection is regulated by hepatic immune defences triggered by the cellular RIG-I helicase. RIG-I binds PAMP RNA and signals interferon regulatory factor 3 activation to induce the expression of interferon-alpha/beta and antiviral/interferon-stimulated genes (ISGs) that limit infection. Here we identify the polyuridine motif of the HCV genome 3' non-translated region and its replication intermediate as the PAMP substrate of RIG-I, and show that this and similar homopolyuridine or homopolyriboadenine motifs present in the genomes of RNA viruses are the chief feature of RIG-I recognition and immune triggering in human and murine cells. 5' terminal triphosphate on the PAMP RNA was necessary but not sufficient for RIG-I binding, which was primarily dependent on homopolymeric ribonucleotide composition, linear structure and length. The HCV PAMP RNA stimulated RIG-I-dependent signalling to induce a hepatic innate immune response in vivo, and triggered interferon and ISG expression to suppress HCV infection in vitro. These results provide a conceptual advance by defining specific homopolymeric RNA motifs within the genome of HCV and other RNA viruses as the PAMP substrate of RIG-I, and demonstrate immunogenic features of the PAMP-RIG-I interaction that could be used as an immune adjuvant for vaccine and immunotherapy approaches.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856441/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856441/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Saito, Takeshi -- Owen, David M -- Jiang, Fuguo -- Marcotrigiano, Joseph -- Gale, Michael Jr -- P01 DA021353/DA/NIDA NIH HHS/ -- R01 AI060389/AI/NIAID NIH HHS/ -- R01 AI060389-01/AI/NIAID NIH HHS/ -- R01 AI060389-02/AI/NIAID NIH HHS/ -- R01 AI060389-03/AI/NIAID NIH HHS/ -- R01 AI060389-04/AI/NIAID NIH HHS/ -- R01 AI060389-05/AI/NIAID NIH HHS/ -- R01 AI060389-06/AI/NIAID NIH HHS/ -- R01 AI060389-07/AI/NIAID NIH HHS/ -- R01 AI060389-08/AI/NIAID NIH HHS/ -- R01 AI060389-09/AI/NIAID NIH HHS/ -- R01 DA024563/DA/NIDA NIH HHS/ -- R01 DA024563-01/DA/NIDA NIH HHS/ -- R01 DA024563-02/DA/NIDA NIH HHS/ -- R01 DA024563-03/DA/NIDA NIH HHS/ -- R01AI060389/AI/NIAID NIH HHS/ -- R01DA021353/DA/NIDA NIH HHS/ -- U19 AI040035/AI/NIAID NIH HHS/ -- U19 AI040035-100004/AI/NIAID NIH HHS/ -- U19 AI040035-110004/AI/NIAID NIH HHS/ -- U19 AI040035-120004/AI/NIAID NIH HHS/ -- U19 AI040035-130004/AI/NIAID NIH HHS/ -- U19 AI040035-140004/AI/NIAID NIH HHS/ -- U19AI40035/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Jul 24;454(7203):523-7. doi: 10.1038/nature07106. Epub 2008 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195-7650, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18548002" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/immunology/metabolism ; Animals ; Cell Line ; DEAD-box RNA Helicases/deficiency/genetics/*metabolism ; Genome, Viral/genetics ; Hepacivirus/*genetics/*immunology/pathogenicity ; Humans ; Immunity, Innate/*immunology ; Interferon-beta/biosynthesis/genetics/immunology ; Ligands ; Liver/immunology/virology ; Mice ; RNA, Viral/*genetics/*immunology ; Uridine/genetics/immunology/metabolism ; Virus Replication/genetics
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    Draper-dependent glial phagocytic activity is mediated by Src and Syk family kinase signalling (2008)
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    Publication Date: 2008-04-25
    Description: The cellular machinery promoting phagocytosis of corpses of apoptotic cells is well conserved from worms to mammals. An important component is the Caenorhabditis elegans engulfment receptor CED-1 (ref. 1) and its Drosophila orthologue, Draper. The CED-1/Draper signalling pathway is also essential for the phagocytosis of other types of 'modified self' including necrotic cells, developmentally pruned axons and dendrites, and axons undergoing Wallerian degeneration. Here we show that Drosophila Shark, a non-receptor tyrosine kinase similar to mammalian Syk and Zap-70, binds Draper through an immunoreceptor tyrosine-based activation motif (ITAM) in the Draper intracellular domain. We show that Shark activity is essential for Draper-mediated signalling events in vivo, including the recruitment of glial membranes to severed axons and the phagocytosis of axonal debris and neuronal cell corpses by glia. We also show that the Src family kinase (SFK) Src42A can markedly increase Draper phosphorylation and is essential for glial phagocytic activity. We propose that ligand-dependent Draper receptor activation initiates the Src42A-dependent tyrosine phosphorylation of Draper, the association of Shark and the activation of the Draper pathway. These Draper-Src42A-Shark interactions are strikingly similar to mammalian immunoreceptor-SFK-Syk signalling events in mammalian myeloid and lymphoid cells. Thus, Draper seems to be an ancient immunoreceptor with an extracellular domain tuned to modified self, and an intracellular domain promoting phagocytosis through an ITAM-domain-SFK-Syk-mediated signalling cascade.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493287/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2493287/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ziegenfuss, Jennifer S -- Biswas, Romi -- Avery, Michelle A -- Hong, Kyoungja -- Sheehan, Amy E -- Yeung, Yee-Guide -- Stanley, E Richard -- Freeman, Marc R -- 1R01CA26504/CA/NCI NIH HHS/ -- 1R01GM55293/GM/NIGMS NIH HHS/ -- 1R01NS053538/NS/NINDS NIH HHS/ -- R37 CA026504/CA/NCI NIH HHS/ -- R37 CA026504-30/CA/NCI NIH HHS/ -- England -- Nature. 2008 Jun 12;453(7197):935-9. doi: 10.1038/nature06901. Epub 2008 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, Massachusetts 01605-2324, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18432193" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Axons/metabolism/pathology ; Cell Line ; Cell Membrane/metabolism ; Central Nervous System ; Drosophila Proteins/chemistry/*metabolism ; Intracellular Signaling Peptides and Proteins/*metabolism ; Membrane Proteins/chemistry/*metabolism ; Neuroglia/*cytology ; *Phagocytosis ; Phosphorylation ; Protein Binding ; Protein Structure, Tertiary ; Protein Transport ; Protein-Tyrosine Kinases/*metabolism ; Proto-Oncogene Proteins pp60(c-src)/*metabolism ; *Signal Transduction ; Two-Hybrid System Techniques
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    Regulatory networks define phenotypic classes of human stem cell lines (2008)
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    Publication Date: 2008-08-30
    Description: Stem cells are defined as self-renewing cell populations that can differentiate into multiple distinct cell types. However, hundreds of different human cell lines from embryonic, fetal and adult sources have been called stem cells, even though they range from pluripotent cells-typified by embryonic stem cells, which are capable of virtually unlimited proliferation and differentiation-to adult stem cell lines, which can generate a far more limited repertoire of differentiated cell types. The rapid increase in reports of new sources of stem cells and their anticipated value to regenerative medicine has highlighted the need for a general, reproducible method for classification of these cells. We report here the creation and analysis of a database of global gene expression profiles (which we call the 'stem cell matrix') that enables the classification of cultured human stem cells in the context of a wide variety of pluripotent, multipotent and differentiated cell types. Using an unsupervised clustering method to categorize a collection of approximately 150 cell samples, we discovered that pluripotent stem cell lines group together, whereas other cell types, including brain-derived neural stem cell lines, are very diverse. Using further bioinformatic analysis we uncovered a protein-protein network (PluriNet) that is shared by the pluripotent cells (embryonic stem cells, embryonal carcinomas and induced pluripotent cells). Analysis of published data showed that the PluriNet seems to be a common characteristic of pluripotent cells, including mouse embryonic stem and induced pluripotent cells and human oocytes. Our results offer a new strategy for classifying stem cells and support the idea that pluripotency and self-renewal are under tight control by specific molecular networks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2637443/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2637443/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muller, Franz-Josef -- Laurent, Louise C -- Kostka, Dennis -- Ulitsky, Igor -- Williams, Roy -- Lu, Christina -- Park, In-Hyun -- Rao, Mahendra S -- Shamir, Ron -- Schwartz, Philip H -- Schmidt, Nils O -- Loring, Jeanne F -- K12 5K12HD000849-20/HD/NICHD NIH HHS/ -- P20 GM075059/GM/NIGMS NIH HHS/ -- P20 GM075059-01/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Sep 18;455(7211):401-5. doi: 10.1038/nature07213. Epub 2008 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Regenerative Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. fj.mueller@zip-kiel.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18724358" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Animals ; Artificial Intelligence ; Cell Differentiation ; Cell Line ; Computational Biology ; Databases, Factual ; Embryonic Stem Cells/classification/metabolism ; *Gene Expression Profiling ; Humans ; Mice ; Multipotent Stem Cells/classification/metabolism ; Oligonucleotide Array Sequence Analysis ; Oocytes/classification/metabolism ; Phenotype ; Pluripotent Stem Cells/classification/metabolism ; Protein Binding ; Stem Cells/*classification/*metabolism
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    The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response (2008)
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    Publication Date: 2008-02-22
    Description: The innate immune system recognizes nucleic acids during infection and tissue damage. Whereas viral RNA is detected by endosomal toll-like receptors (TLR3, TLR7, TLR8) and cytoplasmic RIG-I and MDA5, endosomal TLR9 and cytoplasmic DAI bind DNA, resulting in the activation of nuclear factor-kappaB and interferon regulatory factor transcription factors. However, viruses also trigger pro-inflammatory responses, which remain poorly defined. Here we show that internalized adenoviral DNA induces maturation of pro-interleukin-1beta in macrophages, which is dependent on NALP3 and ASC, components of the innate cytosolic molecular complex termed the inflammasome. Correspondingly, NALP3- and ASC-deficient mice display reduced innate inflammatory responses to adenovirus particles. Inflammasome activation also occurs as a result of transfected cytosolic bacterial, viral and mammalian (host) DNA, but in this case sensing is dependent on ASC but not NALP3. The DNA-sensing pro-inflammatory pathway functions independently of TLRs and interferon regulatory factors. Thus, in addition to viral and bacterial components or danger signals in general, inflammasomes sense potentially dangerous cytoplasmic DNA, strengthening their central role in innate immunity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muruve, Daniel A -- Petrilli, Virginie -- Zaiss, Anne K -- White, Lindsay R -- Clark, Sharon A -- Ross, P Joel -- Parks, Robin J -- Tschopp, Jurg -- England -- Nature. 2008 Mar 6;452(7183):103-7. doi: 10.1038/nature06664. Epub 2008 Feb 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Calgary, Alberta T2N 4N1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18288107" target="_blank"〉PubMed〈/a〉
    Keywords: Adenoviridae/genetics/immunology/physiology ; Animals ; Apoptosis Regulatory Proteins ; Carrier Proteins/genetics/*immunology ; Cell Line ; Cytoskeletal Proteins/deficiency/genetics/*immunology ; Cytosol/*metabolism/microbiology/*virology ; DNA/*immunology ; DNA, Viral/immunology ; Humans ; Immunity, Innate/*immunology ; Inflammation/*immunology/virology ; Interleukin-1beta/immunology/metabolism/secretion ; Macrophages, Peritoneal/immunology/metabolism ; Mice ; Mice, Inbred C57BL ; Protein Processing, Post-Translational
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    The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel (2008)
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    Publication Date: 2008-09-17
    Description: TRPML1 (mucolipin 1, also known as MCOLN1) is predicted to be an intracellular late endosomal and lysosomal ion channel protein that belongs to the mucolipin subfamily of transient receptor potential (TRP) proteins. Mutations in the human TRPML1 gene cause mucolipidosis type IV disease (ML4). ML4 patients have motor impairment, mental retardation, retinal degeneration and iron-deficiency anaemia. Because aberrant iron metabolism may cause neural and retinal degeneration, it may be a primary cause of ML4 phenotypes. In most mammalian cells, release of iron from endosomes and lysosomes after iron uptake by endocytosis of Fe(3+)-bound transferrin receptors, or after lysosomal degradation of ferritin-iron complexes and autophagic ingestion of iron-containing macromolecules, is the chief source of cellular iron. The divalent metal transporter protein DMT1 (also known as SLC11A2) is the only endosomal Fe(2+) transporter known at present and it is highly expressed in erythroid precursors. Genetic studies, however, suggest the existence of a DMT1-independent endosomal and lysosomal Fe(2+) transport protein. By measuring radiolabelled iron uptake, by monitoring the levels of cytosolic and intralysosomal iron and by directly patch-clamping the late endosomal and lysosomal membrane, here we show that TRPML1 functions as a Fe(2+) permeable channel in late endosomes and lysosomes. ML4 mutations are shown to impair the ability of TRPML1 to permeate Fe(2+) at varying degrees, which correlate well with the disease severity. A comparison of TRPML1(-/- )ML4 and control human skin fibroblasts showed a reduction in cytosolic Fe(2+) levels, an increase in intralysosomal Fe(2+) levels and an accumulation of lipofuscin-like molecules in TRPML1(-/-) cells. We propose that TRPML1 mediates a mechanism by which Fe(2+) is released from late endosomes and lysosomes. Our results indicate that impaired iron transport may contribute to both haematological and degenerative symptoms of ML4 patients.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301259/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301259/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Xian-Ping -- Cheng, Xiping -- Mills, Eric -- Delling, Markus -- Wang, Fudi -- Kurz, Tino -- Xu, Haoxing -- T32 HL007572/HL/NHLBI NIH HHS/ -- England -- Nature. 2008 Oct 16;455(7215):992-6. doi: 10.1038/nature07311. Epub 2008 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Department of Molecular, Cellular, and Developmental Biology, The University of Michigan, 3089 Natural Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18794901" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Membrane Permeability ; Endosomes/*metabolism ; Fibroblasts ; Fluorescence ; Humans ; Ion Transport ; Iron/analysis/*metabolism ; Lysosomes/*metabolism ; Mice ; Mucolipidoses/*metabolism ; Protons ; TRPM Cation Channels/deficiency/genetics/*metabolism ; Transfection ; Transient Receptor Potential Channels
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    On the nature of partial agonism in the nicotinic receptor superfamily (2008)
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    Publication Date: 2008-07-18
    Description: Partial agonists are ligands that bind to receptors but produce only a small maximum response even at concentrations where all receptors are occupied. In the case of ligand-activated ion channels, it has been supposed since 1957 that partial agonists evoke a small response because they are inefficient at eliciting the change of conformation between shut and open states of the channel. We have investigated partial agonists for two members of the nicotinic superfamily-the muscle nicotinic acetylcholine receptor and the glycine receptor-and find that the open-shut reaction is similar for both full and partial agonists, but the response to partial agonists is limited by an earlier conformation change ('flipping') that takes place while the channel is still shut. This has implications for the interpretation of structural studies, and in the future, for the design of partial agonists for therapeutic use.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629928/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629928/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lape, Remigijus -- Colquhoun, David -- Sivilotti, Lucia G -- 074491/Wellcome Trust/United Kingdom -- G0400869/Medical Research Council/United Kingdom -- G0400869(72542)/Medical Research Council/United Kingdom -- England -- Nature. 2008 Aug 7;454(7205):722-7. doi: 10.1038/nature07139. Epub 2008 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18633353" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; *Drug Partial Agonism ; Glycine/pharmacology ; Humans ; Membrane Potentials/drug effects ; Muscles/metabolism ; Nicotinic Agonists/*pharmacology ; Protein Conformation ; Protein Subunits/agonists/chemistry/genetics/metabolism ; Quaternary Ammonium Compounds/pharmacology ; Rats ; Receptors, Glycine/agonists/chemistry/genetics/metabolism ; Receptors, Nicotinic/chemistry/genetics/*metabolism ; Structure-Activity Relationship ; Taurine/pharmacology
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    Drosophila Pgc protein inhibits P-TEFb recruitment to chromatin in primordial germ cells (2008)
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    Publication Date: 2008-01-18
    Description: Germ cells are the only cells that transmit genetic information to the next generation, and they therefore must be prevented from differentiating inappropriately into somatic cells. A common mechanism by which germline progenitors are protected from differentiation-inducing signals is a transient and global repression of RNA polymerase II (RNAPII)-dependent transcription. In both Drosophila and Caenorhabditis elegans embryos, the repression of messenger RNA transcription during germ cell specification correlates with an absence of phosphorylation of Ser 2 residues in the carboxy-terminal domain of RNAPII (hereafter called CTD), a critical modification for transcriptional elongation. Here we show that, in Drosophila embryos, a small protein encoded by polar granule component (pgc) is essential for repressing CTD Ser 2 phosphorylation in newly formed pole cells, the germline progenitors. Ectopic Pgc expression in somatic cells is sufficient to repress CTD Ser 2 phosphorylation. Furthermore, Pgc interacts, physically and genetically, with positive transcription elongation factor b (P-TEFb), the CTD Ser 2 kinase complex, and prevents its recruitment to transcription sites. These results indicate that Pgc is a cell-type-specific P-TEFb inhibitor that has a fundamental role in Drosophila germ cell specification. In C. elegans embryos, PIE-1 protein segregates to germline blastomeres, and is thought to repress mRNA transcription through interaction with P-TEFb. Thus, inhibition of P-TEFb is probably a common mechanism during germ cell specification in the disparate organisms C. elegans and Drosophila.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719856/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2719856/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hanyu-Nakamura, Kazuko -- Sonobe-Nojima, Hiroko -- Tanigawa, Akie -- Lasko, Paul -- Nakamura, Akira -- R01 HD036631/HD/NICHD NIH HHS/ -- R01 HD036631-10/HD/NICHD NIH HHS/ -- England -- Nature. 2008 Feb 7;451(7179):730-3. doi: 10.1038/nature06498. Epub 2008 Jan 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Germline Development, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18200011" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans ; Cell Line ; Chromatin/genetics/*metabolism ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*cytology/embryology/genetics/*metabolism ; Gene Expression Regulation, Developmental ; Germ Cells/cytology/*metabolism ; Phosphorylation ; Phosphoserine/metabolism ; Positive Transcriptional Elongation Factor B/antagonists & ; inhibitors/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; RNA Polymerase II/chemistry/metabolism ; Stem Cells/cytology/metabolism
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    Drosophila RNAi screen identifies host genes important for influenza virus replication (2008)
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    Publication Date: 2008-07-11
    Description: All viruses rely on host cell proteins and their associated mechanisms to complete the viral life cycle. Identifying the host molecules that participate in each step of virus replication could provide valuable new targets for antiviral therapy, but this goal may take several decades to achieve with conventional forward genetic screening methods and mammalian cell cultures. Here we describe a novel genome-wide RNA interference (RNAi) screen in Drosophila that can be used to identify host genes important for influenza virus replication. After modifying influenza virus to allow infection of Drosophila cells and detection of influenza virus gene expression, we tested an RNAi library against 13,071 genes (90% of the Drosophila genome), identifying over 100 for which suppression in Drosophila cells significantly inhibited or stimulated reporter gene (Renilla luciferase) expression from an influenza-virus-derived vector. The relevance of these findings to influenza virus infection of mammalian cells is illustrated for a subset of the Drosophila genes identified; that is, for three implicated Drosophila genes, the corresponding human homologues ATP6V0D1, COX6A1 and NXF1 are shown to have key functions in the replication of H5N1 and H1N1 influenza A viruses, but not vesicular stomatitis virus or vaccinia virus, in human HEK 293 cells. Thus, we have demonstrated the feasibility of using genome-wide RNAi screens in Drosophila to identify previously unrecognized host proteins that are required for influenza virus replication. This could accelerate the development of new classes of antiviral drugs for chemoprophylaxis and treatment, which are urgently needed given the obstacles to rapid development of an effective vaccine against pandemic influenza and the probable emergence of strains resistant to available drugs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574945/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574945/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hao, Linhui -- Sakurai, Akira -- Watanabe, Tokiko -- Sorensen, Ericka -- Nidom, Chairul A -- Newton, Michael A -- Ahlquist, Paul -- Kawaoka, Yoshihiro -- GM35072/GM/NIGMS NIH HHS/ -- R01 AI044386/AI/NIAID NIH HHS/ -- R01 AI044386-10/AI/NIAID NIH HHS/ -- R01 AI047446/AI/NIAID NIH HHS/ -- R01 AI047446-09/AI/NIAID NIH HHS/ -- R01 AI069274/AI/NIAID NIH HHS/ -- R01 AI069274-03/AI/NIAID NIH HHS/ -- R01 GM035072/GM/NIGMS NIH HHS/ -- R01 GM035072-23/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Aug 14;454(7206):890-3. doi: 10.1038/nature07151. Epub 2008 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Molecular Virology, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18615016" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Drosophila melanogaster/*genetics/*virology ; Gene Expression Regulation ; Genome, Insect/genetics ; Host-Pathogen Interactions/*physiology ; Humans ; Influenza A virus/*physiology ; Luciferases, Renilla/metabolism ; *RNA Interference ; Vaccinia virus/physiology ; Vesiculovirus/physiology ; Virus Replication/*physiology
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    Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu (2008)
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    Publication Date: 2008-01-18
    Description: Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha, and it consists of protein-based tethers, which we term 'tetherins', that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherin's antiviral activity is a potential therapeutic strategy in HIV/AIDS.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neil, Stuart J D -- Zang, Trinity -- Bieniasz, Paul D -- England -- Nature. 2008 Jan 24;451(7177):425-30. doi: 10.1038/nature06553. Epub 2008 Jan 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Aaron Diamond AIDS Research Center and Laboratory of Retrovirology, The Rockefeller University, 455 First Avenue, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18200009" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, CD/genetics/*metabolism ; Cell Line ; Cell Membrane/virology ; Endocytosis ; GPI-Linked Proteins ; Gene Expression Profiling ; HIV Infections/metabolism/therapy/virology ; HIV-1/*metabolism ; HeLa Cells ; Human Immunodeficiency Virus Proteins/antagonists & inhibitors/*metabolism ; Humans ; Interferon-alpha/pharmacology ; Leukemia Virus, Murine/metabolism ; Membrane Glycoproteins/*antagonists & inhibitors/genetics/*metabolism ; Mutant Proteins/genetics/metabolism ; Oligonucleotide Array Sequence Analysis ; Protein Transport ; Viral Regulatory and Accessory Proteins/antagonists & inhibitors/*metabolism ; Virion/metabolism ; Virus Replication ; gag Gene Products, Human Immunodeficiency Virus/metabolism
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    A novel route for ATP acquisition by the remnant mitochondria of Encephalitozoon cuniculi (2008)
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    Publication Date: 2008-05-02
    Description: Mitochondria use transport proteins of the eukaryotic mitochondrial carrier family (MCF) to mediate the exchange of diverse substrates, including ATP, with the host cell cytosol. According to classical endosymbiosis theory, insertion of a host-nuclear-encoded MCF transporter into the protomitochondrion was the key step that allowed the host cell to harvest ATP from the enslaved endosymbiont. Notably the genome of the microsporidian Encephalitozoon cuniculi has lost all of its genes for MCF proteins. This raises the question of how the recently discovered microsporidian remnant mitochondrion, called a mitosome, acquires ATP to support protein import and other predicted ATP-dependent activities. The E. cuniculi genome does contain four genes for an unrelated type of nucleotide transporter used by plastids and bacterial intracellular parasites, such as Rickettsia and Chlamydia, to import ATP from the cytosol of their eukaryotic host cells. The inference is that E. cuniculi also uses these proteins to steal ATP from its eukaryotic host to sustain its lifestyle as an obligate intracellular parasite. Here we show that, consistent with this hypothesis, all four E. cuniculi transporters can transport ATP, and three of them are expressed on the surface of the parasite when it is living inside host cells. The fourth transporter co-locates with mitochondrial Hsp70 to the E. cuniculi mitosome. Thus, uniquely among eukaryotes, the traditional relationship between mitochondrion and host has been subverted in E. cuniculi, by reductive evolution and analogous gene replacement. Instead of the mitosome providing the parasite cytosol with ATP, the parasite cytosol now seems to provide ATP for the organelle.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsaousis, Anastasios D -- Kunji, Edmund R S -- Goldberg, Alina V -- Lucocq, John M -- Hirt, Robert P -- Embley, T Martin -- MC_U105663139/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2008 May 22;453(7194):553-6. doi: 10.1038/nature06903. Epub 2008 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cell and Molecular Biosciences, Catherine Cookson Building, Framlington Place, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18449191" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/*metabolism ; Animals ; Biological Transport ; Carrier Proteins/genetics/immunology/metabolism ; Cell Line ; Encephalitozoon cuniculi/*cytology/genetics/*metabolism ; Escherichia coli/genetics/metabolism ; Fungal Proteins/genetics/immunology/metabolism ; Genome, Fungal/genetics ; Genome, Mitochondrial/genetics ; Mitochondria/genetics/*metabolism ; Models, Biological ; Molecular Sequence Data ; Rabbits ; Rats ; Symbiosis
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    New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure (2008)
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    Publication Date: 2008-08-23
    Description: Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue, which is specialized in energy expenditure and can counteract obesity. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood. Here we demonstrate that whereas some members of the family of bone morphogenetic proteins (BMPs) support white adipocyte differentiation, BMP7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM16 (PR-domain-containing 16; ref. 4) and PGC-1alpha (peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator-1alpha; ref. 5), increased expression of the brown-fat-defining marker uncoupling protein 1 (UCP1) and adipogenic transcription factors PPARgamma and CCAAT/enhancer-binding proteins (C/EBPs), and induction of mitochondrial biogenesis via p38 mitogen-activated protein (MAP) kinase-(also known as Mapk14) and PGC-1-dependent pathways. Moreover, BMP7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. Bmp7 knockout embryos show a marked paucity of brown fat and an almost complete absence of UCP1. Adenoviral-mediated expression of BMP7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and a reduction in weight gain. These data reveal an important role of BMP7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential new therapeutic approach for the treatment of obesity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745972/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745972/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tseng, Yu-Hua -- Kokkotou, Efi -- Schulz, Tim J -- Huang, Tian Lian -- Winnay, Jonathon N -- Taniguchi, Cullen M -- Tran, T Thien -- Suzuki, Ryo -- Espinoza, Daniel O -- Yamamoto, Yuji -- Ahrens, Molly J -- Dudley, Andrew T -- Norris, Andrew W -- Kulkarni, Rohit N -- Kahn, C Ronald -- K08 DK064906/DK/NIDDK NIH HHS/ -- K08 DK64906/DK/NIDDK NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- P30 DK46200/DK/NIDDK NIH HHS/ -- R01 DK 060837/DK/NIDDK NIH HHS/ -- R01 DK077097/DK/NIDDK NIH HHS/ -- R01 DK077097-01A1/DK/NIDDK NIH HHS/ -- R01 DK077097-02/DK/NIDDK NIH HHS/ -- R01 DK67536/DK/NIDDK NIH HHS/ -- R21 DK070722/DK/NIDDK NIH HHS/ -- R21 DK070722-01/DK/NIDDK NIH HHS/ -- R21 DK070722-02/DK/NIDDK NIH HHS/ -- England -- Nature. 2008 Aug 21;454(7207):1000-4. doi: 10.1038/nature07221.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section on Obesity and Hormone Action, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA. yu-hua.tseng@joslin.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18719589" target="_blank"〉PubMed〈/a〉
    Keywords: 3T3-L1 Cells ; *Adipogenesis ; Adipose Tissue, Brown/*growth & development/*metabolism ; Adipose Tissue, White/growth & development ; Animals ; Bone Morphogenetic Protein 7 ; Bone Morphogenetic Proteins/*metabolism ; Cell Line ; *Energy Metabolism/genetics ; Male ; Mesenchymal Stromal Cells/cytology/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Nude ; Mitochondria/physiology ; Thermogenesis ; Transforming Growth Factor beta/*metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
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    Insect olfactory receptors are heteromeric ligand-gated ion channels (2008)
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    Publication Date: 2008-04-15
    Description: In insects, each olfactory sensory neuron expresses between one and three ligand-binding members of the olfactory receptor (OR) gene family, along with the highly conserved and broadly expressed Or83b co-receptor. The functional insect OR consists of a heteromeric complex of unknown stoichiometry but comprising at least one variable odorant-binding subunit and one constant Or83b family subunit. Insect ORs lack homology to G-protein-coupled chemosensory receptors in vertebrates and possess a distinct seven-transmembrane topology with the amino terminus located intracellularly. Here we provide evidence that heteromeric insect ORs comprise a new class of ligand-activated non-selective cation channels. Heterologous cells expressing silkmoth, fruitfly or mosquito heteromeric OR complexes showed extracellular Ca2+ influx and cation-non-selective ion conductance on stimulation with odorant. Odour-evoked OR currents are independent of known G-protein-coupled second messenger pathways. The fast response kinetics and OR-subunit-dependent K+ ion selectivity of the insect OR complex support the hypothesis that the complex between OR and Or83b itself confers channel activity. Direct evidence for odorant-gated channels was obtained by outside-out patch-clamp recording of Xenopus oocyte and HEK293T cell membranes expressing insect OR complexes. The ligand-gated ion channel formed by an insect OR complex seems to be the basis for a unique strategy that insects have acquired to respond to the olfactory environment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sato, Koji -- Pellegrino, Maurizio -- Nakagawa, Takao -- Nakagawa, Tatsuro -- Vosshall, Leslie B -- Touhara, Kazushige -- England -- Nature. 2008 Apr 24;452(7190):1002-6. doi: 10.1038/nature06850. Epub 2008 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrated Biosciences, The University of Tokyo, Chiba 277-8562, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18408712" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bombyx ; Calcium/metabolism ; Cell Line ; Culicidae ; Drosophila melanogaster ; Electric Conductivity ; HeLa Cells ; Heterotrimeric GTP-Binding Proteins ; Humans ; Insects/*chemistry ; *Ion Channel Gating ; Kinetics ; Ligands ; Odors/analysis ; Oocytes/metabolism ; Patch-Clamp Techniques ; Protein Subunits/chemistry/metabolism ; Receptors, Odorant/*chemistry/*metabolism ; Smell ; Xenopus laevis
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