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  • 101
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    Immunology: Oxysterols hold T cells in check (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-09-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Glass, Christopher K -- Saijo, Kaoru -- England -- Nature. 2008 Sep 4;455(7209):40-1. doi: 10.1038/455040a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18769427" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Division ; Cholesterol/biosynthesis/*metabolism ; DNA-Binding Proteins/deficiency/*metabolism ; Lymphocyte Activation ; Mice ; Orphan Nuclear Receptors ; Receptors, Cytoplasmic and Nuclear/deficiency/*metabolism ; Sulfotransferases/metabolism ; T-Lymphocytes/*cytology/*immunology/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 102
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    Oligopotent stem cells are distributed throughout the mammalian ocular surface (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-10-03
    Description: The integrity of the cornea, the most anterior part of the eye, is indispensable for vision. Forty-five million individuals worldwide are bilaterally blind and another 135 million have severely impaired vision in both eyes because of loss of corneal transparency; treatments range from local medications to corneal transplants, and more recently to stem cell therapy. The corneal epithelium is a squamous epithelium that is constantly renewing, with a vertical turnover of 7 to 14 days in many mammals. Identification of slow cycling cells (label-retaining cells) in the limbus of the mouse has led to the notion that the limbus is the niche for the stem cells responsible for the long-term renewal of the cornea; hence, the corneal epithelium is supposedly renewed by cells generated at and migrating from the limbus, in marked opposition to other squamous epithelia in which each resident stem cell has in charge a limited area of epithelium. Here we show that the corneal epithelium of the mouse can be serially transplanted, is self-maintained and contains oligopotent stem cells with the capacity to generate goblet cells if provided with a conjunctival environment. Furthermore, the entire ocular surface of the pig, including the cornea, contains oligopotent stem cells (holoclones) with the capacity to generate individual colonies of corneal and conjunctival cells. Therefore, the limbus is not the only niche for corneal stem cells and corneal renewal is not different from other squamous epithelia. We propose a model that unifies our observations with the literature and explains why the limbal region is enriched in stem cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Majo, Francois -- Rochat, Ariane -- Nicolas, Michael -- Jaoude, Georges Abou -- Barrandon, Yann -- England -- Nature. 2008 Nov 13;456(7219):250-4. doi: 10.1038/nature07406. Epub 2008 Oct 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Stem Cell Dynamics, Ecole Polytechnique Federale de Lausanne (EPFL), 1015 Lausanne CH, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18830243" target="_blank"〉PubMed〈/a〉
    Keywords: Adult Stem Cells/*cytology ; Animals ; Cattle ; Cells, Cultured ; Child, Preschool ; Clone Cells ; Corneal Transplantation ; Epithelium, Corneal/*cytology/metabolism ; Female ; Gene Expression Regulation ; Humans ; Infant ; Keratinocytes/cytology/metabolism ; Male ; Mice ; Mice, SCID ; Models, Biological ; Multipotent Stem Cells/*cytology ; Proteins/metabolism ; Rats ; Swine
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 103
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    Cancer: Ins and outs of tumour control (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soengas, Maria S -- England -- Nature. 2008 Jul 31;454(7204):586-7. doi: 10.1038/454586a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18668094" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/genetics ; CCAAT-Enhancer-Binding Proteins/genetics/metabolism ; Cell Aging/genetics ; Humans ; Interleukin-6/genetics ; Interleukin-8/genetics ; Mice ; NF-kappa B/metabolism ; Neoplasms/genetics/*immunology/metabolism/*pathology ; Proto-Oncogene Proteins B-raf/genetics/metabolism ; Receptors, Interleukin-8B/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 104
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    Internal brain state regulates membrane potential synchrony in barrel cortex of behaving mice (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-07-18
    Description: Internal brain states form key determinants for sensory perception, sensorimotor coordination and learning. A prominent reflection of different brain states in the mammalian central nervous system is the presence of distinct patterns of cortical synchrony, as revealed by extracellular recordings of the electroencephalogram, local field potential and action potentials. Such temporal correlations of cortical activity are thought to be fundamental mechanisms of neuronal computation. However, it is unknown how cortical synchrony is reflected in the intracellular membrane potential (V(m)) dynamics of behaving animals. Here we show, using dual whole-cell recordings from layer 2/3 primary somatosensory barrel cortex in behaving mice, that the V(m) of nearby neurons is highly correlated during quiet wakefulness. However, when the mouse is whisking, an internally generated state change reduces the V(m) correlation, resulting in a desynchronized local field potential and electroencephalogram. Action potential activity was sparse during both quiet wakefulness and active whisking. Single action potentials were driven by a large, brief and specific excitatory input that was not present in the V(m) of neighbouring cells. Action potential initiation occurs with a higher signal-to-noise ratio during active whisking than during quiet periods. Therefore, we show that an internal brain state dynamically regulates cortical membrane potential synchrony during behaviour and defines different modes of cortical processing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poulet, James F A -- Petersen, Carl C H -- England -- Nature. 2008 Aug 14;454(7206):881-5. doi: 10.1038/nature07150. Epub 2008 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Sensory Processing, Brain Mind Institute, Faculty of Life Sciences, Ecole Polytechnique Federale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18633351" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Electroencephalography ; Exploratory Behavior/*physiology ; Male ; Membrane Potentials/*physiology ; Mice ; Mice, Inbred C57BL ; Neurons/*physiology ; Somatosensory Cortex/*physiology ; Wakefulness/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 105
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    Fertilization: Welcome to the fold (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-12-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wassarman, Paul M -- England -- Nature. 2008 Dec 4;456(7222):586-7. doi: 10.1038/456586a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052615" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Conserved Sequence ; Crystallography, X-Ray ; Egg Proteins/*chemistry/genetics/*metabolism ; Female ; Fertilization/physiology ; Male ; Membrane Glycoproteins/*chemistry/genetics/*metabolism ; Mice ; Ovum/*chemistry/*metabolism ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Cell Surface/*chemistry/genetics/*metabolism ; Spermatozoa/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 106
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    Endothelins are vascular-derived axonal guidance cues for developing sympathetic neurons (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-04-11
    Description: During development, sympathetic neurons extend axons along a myriad of distinct trajectories, often consisting of arteries, to innervate one of a large variety of distinct final target tissues. Whether or not subsets of neurons within complex sympathetic ganglia are predetermined to innervate select end-organs is unknown. Here we demonstrate in mouse embryos that the endothelin family member Edn3 (ref. 1), acting through the endothelin receptor EdnrA (refs 2, 3), directs extension of axons of a subset of sympathetic neurons from the superior cervical ganglion to a preferred intermediate target, the external carotid artery, which serves as the gateway to select targets, including the salivary glands. These findings establish a previously unknown mechanism of axonal pathfinding involving vascular-derived endothelins, and have broad implications for endothelins as general mediators of axonal growth and guidance in the developing nervous system. Moreover, they suggest a model in which newborn sympathetic neurons distinguish and choose between distinct vascular trajectories to innervate their appropriate end organs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2713667/" 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/PMC2713667/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Makita, Takako -- Sucov, Henry M -- Gariepy, Cheryl E -- Yanagisawa, Masashi -- Ginty, David D -- R01 HL078891/HL/NHLBI NIH HHS/ -- R01 HL078891-01A1/HL/NHLBI NIH HHS/ -- R01 HL078891-02/HL/NHLBI NIH HHS/ -- R01 HL078891-03/HL/NHLBI NIH HHS/ -- R37 NS034814/NS/NINDS NIH HHS/ -- R37 NS034814-11/NS/NINDS NIH HHS/ -- R37 NS034814-11S1/NS/NINDS NIH HHS/ -- R37 NS034814-12/NS/NINDS NIH HHS/ -- R37 NS034814-13/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Apr 10;452(7188):759-63. doi: 10.1038/nature06859.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Solomon H. Snyder Department of Neuroscience, Howard Hughes Medical Institute, The 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/18401410" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/*physiology ; Carotid Arteries/cytology/*metabolism ; Cues ; Embryo, Mammalian/blood supply/cytology ; Endothelin-3/metabolism ; Endothelins/*metabolism ; Mice ; Neurites/physiology ; Receptors, Endothelin/metabolism ; Salivary Glands/innervation ; *Signal Transduction ; Superior Cervical Ganglion/*cytology/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 107
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    Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-04-04
    Description: Continuous turnover of epithelia is ensured by the extensive self-renewal capacity of tissue-specific stem cells. Similarly, epithelial tumour maintenance relies on cancer stem cells (CSCs), which co-opt stem cell properties. For most tumours, the cellular origin of these CSCs and regulatory pathways essential for sustaining stemness have not been identified. In murine skin, follicular morphogenesis is driven by bulge stem cells that specifically express CD34. Here we identify a population of cells in early epidermal tumours characterized by phenotypic and functional similarities to normal bulge skin stem cells. This population contains CSCs, which are the only cells with tumour initiation properties. Transplants derived from these CSCs preserve the hierarchical organization of the primary tumour. We describe beta-catenin signalling as being essential in sustaining the CSC phenotype. Ablation of the beta-catenin gene results in the loss of CSCs and complete tumour regression. In addition, we provide evidence for the involvement of increased beta-catenin signalling in malignant human squamous cell carcinomas. Because Wnt/beta-catenin signalling is not essential for normal epidermal homeostasis, such a mechanistic difference may thus be targeted to eliminate CSCs and consequently eradicate squamous cell carcinomas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Malanchi, Ilaria -- Peinado, Hector -- Kassen, Deepika -- Hussenet, Thomas -- Metzger, Daniel -- Chambon, Pierre -- Huber, Marcel -- Hohl, Daniel -- Cano, Amparo -- Birchmeier, Walter -- Huelsken, Joerg -- England -- Nature. 2008 Apr 3;452(7187):650-3. doi: 10.1038/nature06835.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ecole Polytechnique Federale de Lausanne/ISREC (Swiss Institute for Experimental Cancer Research) and National Center of Competence in Research Molecular Oncology, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18385740" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD34/metabolism ; Cell Line, Tumor ; *Cell Transformation, Neoplastic ; Cells, Cultured ; Epidermis/pathology ; Humans ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Neoplastic Stem Cells/*metabolism/*pathology ; *Signal Transduction ; Skin Neoplasms/*pathology ; beta Catenin/*metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 108
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    Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-04-12
    Description: RNA interference (RNAi) is a mechanism by which double-stranded RNAs (dsRNAs) suppress specific transcripts in a sequence-dependent manner. dsRNAs are processed by Dicer to 21-24-nucleotide small interfering RNAs (siRNAs) and then incorporated into the argonaute (Ago) proteins. Gene regulation by endogenous siRNAs has been observed only in organisms possessing RNA-dependent RNA polymerase (RdRP). In mammals, where no RdRP activity has been found, biogenesis and function of endogenous siRNAs remain largely unknown. Here we show, using mouse oocytes, that endogenous siRNAs are derived from naturally occurring dsRNAs and have roles in the regulation of gene expression. By means of deep sequencing, we identify a large number of both approximately 25-27-nucleotide Piwi-interacting RNAs (piRNAs) and approximately 21-nucleotide siRNAs corresponding to messenger RNAs or retrotransposons in growing oocytes. piRNAs are bound to Mili and have a role in the regulation of retrotransposons. siRNAs are exclusively mapped to retrotransposons or other genomic regions that produce transcripts capable of forming dsRNA structures. Inverted repeat structures, bidirectional transcription and antisense transcripts from various loci are sources of the dsRNAs. Some precursor transcripts of siRNAs are derived from expressed pseudogenes, indicating that one role of pseudogenes is to adjust the level of the founding source mRNA through RNAi. Loss of Dicer or Ago2 results in decreased levels of siRNAs and increased levels of retrotransposon and protein-coding transcripts complementary to the siRNAs. Thus, the RNAi pathway regulates both protein-coding transcripts and retrotransposons in mouse oocytes. Our results reveal a role for endogenous siRNAs in mammalian oocytes and show that organisms lacking RdRP activity can produce functional endogenous siRNAs from naturally occurring dsRNAs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watanabe, Toshiaki -- Totoki, Yasushi -- Toyoda, Atsushi -- Kaneda, Masahiro -- Kuramochi-Miyagawa, Satomi -- Obata, Yayoi -- Chiba, Hatsune -- Kohara, Yuji -- Kono, Tomohiro -- Nakano, Toru -- Surani, M Azim -- Sakaki, Yoshiyuki -- Sasaki, Hiroyuki -- England -- Nature. 2008 May 22;453(7194):539-43. doi: 10.1038/nature06908. Epub 2008 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, Mishima 411-8540, Japan. toshwata@lab.nig.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18404146" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins ; Eukaryotic Initiation Factor-2/deficiency/genetics/metabolism ; Female ; Gene Expression Regulation, Developmental ; Gene Library ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Oocytes/growth & development/*metabolism ; Polymerase Chain Reaction ; Pseudogenes/genetics ; *RNA Interference ; RNA, Double-Stranded/*genetics/*metabolism ; RNA, Messenger/*genetics/metabolism ; RNA, Small Interfering/*genetics/*metabolism ; Retroelements/genetics ; Ribonuclease III/deficiency/genetics/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 109
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    Transient FTY720 treatment promotes immune-mediated clearance of a chronic viral infection (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-16
    Description: For a wide variety of microbial pathogens, the outcome of the infection is indeterminate. In some individuals the microbe is cleared, but in others it establishes a chronic infection, and the factors that tip this balance are often unknown. In a widely used model of chronic viral infection, C57BL/6 mice clear the Armstrong strain of lymphocytic choriomeningitis virus (LCMV), but the clone 13 strain persists. Here we show that the Armstrong strain induces a profound lymphopenia at days 1-3 after infection, but the clone 13 strain does not. If we transiently augment lymphopenia by treating the clone-13-infected mice with the drug FTY720 at days 0-2 after infection, the mice successfully clear the infection by day 30. Clearance does not occur when CD4 T cells are absent at the time of treatment, indicating that the drug is not exerting direct antiviral effects. Notably, FTY720 treatment of an already established persistent infection also leads to viral clearance. In both models, FTY720 treatment preserves or augments LCMV-specific CD4 and CD8 T-cell responses, a result that is counter-intuitive because FTY720 is generally regarded as a new immunosuppressive agent. Because FTY720 targets host pathways that are completely evolutionarily conserved, our results may be translatable into new immunotherapies for the treatment of chronic microbial infections in humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Premenko-Lanier, Mary -- Moseley, Nelson B -- Pruett, Sarah T -- Romagnoli, Pablo A -- Altman, John D -- 5F32AI062002/AI/NIAID NIH HHS/ -- AI042373/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Aug 14;454(7206):894-8. doi: 10.1038/nature07199.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center and Department of Microbiology and Immunology, Yerkes National Primate Research Center and Emory University School of Medicine, 954 Gatewood Road, Atlanta, Georgia 30329, USA. mflanie@emory.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18704087" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chronic Disease ; Fingolimod Hydrochloride ; Lymphocytic Choriomeningitis/complications/*drug therapy/*immunology/prevention & ; control ; Lymphocytic choriomeningitis virus/*immunology/physiology ; Lymphopenia/etiology ; Mice ; Mice, Inbred C57BL ; Propylene Glycols/administration & dosage/*pharmacology/*therapeutic use ; Sphingosine/administration & dosage/*analogs & ; derivatives/pharmacology/therapeutic use ; T-Lymphocytes/drug effects/immunology ; 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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  • 110
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    Platelet-derived growth factor-alpha receptor activation is required for human cytomegalovirus infection (2008)
    Nature Publishing Group (NPG)
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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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  • 111
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    The deubiquitinylation and localization of PTEN are regulated by a HAUSP-PML network (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-22
    Description: Nuclear exclusion of the PTEN (phosphatase and tensin homologue deleted in chromosome 10) tumour suppressor has been associated with cancer progression. However, the mechanisms leading to this aberrant PTEN localization in human cancers are currently unknown. We have previously reported that ubiquitinylation of PTEN at specific lysine residues regulates its nuclear-cytoplasmic partitioning. Here we show that functional promyelocytic leukaemia protein (PML) nuclear bodies co-ordinate PTEN localization by opposing the action of a previously unknown PTEN-deubiquitinylating enzyme, herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), and that the integrity of this molecular framework is required for PTEN to be able to enter the nucleus. We find that PTEN is aberrantly localized in acute promyelocytic leukaemia, in which PML function is disrupted by the PML-RARalpha fusion oncoprotein. Remarkably, treatment with drugs that trigger PML-RARalpha degradation, such as all-trans retinoic acid or arsenic trioxide, restore nuclear PTEN. We demonstrate that PML opposes the activity of HAUSP towards PTEN through a mechanism involving the adaptor protein DAXX (death domain-associated protein). In support of this paradigm, we show that HAUSP is overexpressed in human prostate cancer and is associated with PTEN nuclear exclusion. Thus, our results delineate a previously unknown PML-DAXX-HAUSP molecular network controlling PTEN deubiquitinylation and trafficking, which is perturbed by oncogenic cues in human cancer, in turn defining a new deubiquitinylation-dependent model for PTEN subcellular compartmentalization.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398484/" 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/PMC3398484/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Song, Min Sup -- Salmena, Leonardo -- Carracedo, Arkaitz -- Egia, Ainara -- Lo-Coco, Francesco -- Teruya-Feldstein, Julie -- Pandolfi, Pier Paolo -- P50 CA092629/CA/NCI NIH HHS/ -- P50 CA092629-01/CA/NCI NIH HHS/ -- R01 CA082328/CA/NCI NIH HHS/ -- England -- Nature. 2008 Oct 9;455(7214):813-7. doi: 10.1038/nature07290. Epub 2008 Aug 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genetics Program, Beth Israel Deaconess Cancer Center and 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/18716620" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Apoptosis ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Fibroblasts ; Humans ; Leukemia, Promyelocytic, Acute/metabolism/pathology ; Male ; Mice ; Nuclear Proteins/deficiency/genetics/*metabolism ; PTEN Phosphohydrolase/*metabolism ; Prostatic Neoplasms/metabolism/pathology ; Transcription Factors/deficiency/genetics/*metabolism ; Tretinoin/pharmacology ; Tumor Suppressor Proteins/deficiency/genetics/*metabolism ; Ubiquitin Thiolesterase/*metabolism ; *Ubiquitination ; Ubiquitins/*metabolism
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    Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-07-03
    Description: On activation by receptors, the ubiquitously expressed class IA isoforms (p110alpha and p110beta) of phosphatidylinositol-3-OH kinase (PI(3)K) generate lipid second messengers, which initiate multiple signal transduction cascades. Recent studies have demonstrated specific functions for p110alpha in growth factor and insulin signalling. To probe for distinct functions of p110beta, we constructed conditional knockout mice. Here we show that ablation of p110beta in the livers of the resulting mice leads to impaired insulin sensitivity and glucose homeostasis, while having little effect on phosphorylation of Akt, suggesting the involvement of a kinase-independent role of p110beta in insulin metabolic action. Using established mouse embryonic fibroblasts, we found that removal of p110beta also had little effect on Akt phosphorylation in response to stimulation by insulin and epidermal growth factor, but resulted in retarded cell proliferation. Reconstitution of p110beta-null cells with a wild-type or kinase-dead allele of p110beta demonstrated that p110beta possesses kinase-independent functions in regulating cell proliferation and trafficking. However, the kinase activity of p110beta was required for G-protein-coupled receptor signalling triggered by lysophosphatidic acid and had a function in oncogenic transformation. Most strikingly, in an animal model of prostate tumour formation induced by Pten loss, ablation of p110beta (also known as Pik3cb), but not that of p110alpha (also known as Pik3ca), impeded tumorigenesis with a concomitant diminution of Akt phosphorylation. Taken together, our findings demonstrate both kinase-dependent and kinase-independent functions for p110beta, and strongly indicate the kinase-dependent functions of p110beta as a promising target in cancer therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750091/" 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/PMC2750091/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jia, Shidong -- Liu, Zhenning -- Zhang, Sen -- Liu, Pixu -- Zhang, Lei -- Lee, Sang Hyun -- Zhang, Jing -- Signoretti, Sabina -- Loda, Massimo -- Roberts, Thomas M -- Zhao, Jean J -- P01 CA050661/CA/NCI NIH HHS/ -- P01 CA050661-200001/CA/NCI NIH HHS/ -- P01 CA089021/CA/NCI NIH HHS/ -- P01 CA089021-06A1/CA/NCI NIH HHS/ -- P50 CA089393/CA/NCI NIH HHS/ -- P50 CA089393-08S1/CA/NCI NIH HHS/ -- P50 CA090381/CA/NCI NIH HHS/ -- P50 CA090381-05/CA/NCI NIH HHS/ -- R01 CA030002/CA/NCI NIH HHS/ -- R01 CA030002-27/CA/NCI NIH HHS/ -- R01 CA134502/CA/NCI NIH HHS/ -- R01 CA134502-01/CA/NCI NIH HHS/ -- England -- Nature. 2008 Aug 7;454(7205):776-9. doi: 10.1038/nature07091. Epub 2008 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18594509" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Proliferation/drug effects ; *Cell Transformation, Neoplastic ; Epidermal Growth Factor/pharmacology ; Fibroblasts/cytology ; Glucose/*metabolism ; Glucose Intolerance/enzymology/genetics ; Homeostasis ; Humans ; Insulin/*metabolism/pharmacology ; Insulin Resistance/genetics ; Liver/enzymology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; PTEN Phosphohydrolase/deficiency/genetics ; Phosphatidylinositol 3-Kinases/deficiency/genetics/*metabolism ; Phosphorylation/drug effects ; Prostatic Neoplasms/enzymology/genetics/pathology ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction
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    Modelling Myc inhibition as a cancer therapy (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-08-22
    Description: Myc is a pleiotropic basic helix-loop-helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485609/" 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/PMC4485609/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soucek, Laura -- Whitfield, Jonathan -- Martins, Carla P -- Finch, Andrew J -- Murphy, Daniel J -- Sodir, Nicole M -- Karnezis, Anthony N -- Swigart, Lamorna Brown -- Nasi, Sergio -- Evan, Gerard I -- 2R01 CA98018/CA/NCI NIH HHS/ -- R01 CA098018/CA/NCI NIH HHS/ -- R01 CA098018-05/CA/NCI NIH HHS/ -- R01 CA098018-06/CA/NCI NIH HHS/ -- R01 CA098018-07/CA/NCI NIH HHS/ -- T32 CA108462/CA/NCI NIH HHS/ -- T32 CA108462-01/CA/NCI NIH HHS/ -- England -- Nature. 2008 Oct 2;455(7213):679-83. doi: 10.1038/nature07260. Epub 2008 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143-0875, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18716624" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/genetics/metabolism/pathology/therapy ; Animals ; Gastrointestinal Tract/cytology/metabolism/pathology ; Genes, Dominant/genetics ; Genes, ras ; *Genetic Therapy ; Lung Neoplasms/genetics/metabolism/pathology/*therapy ; Male ; Mice ; *Models, Biological ; Mutation/genetics ; Oncogene Protein p21(ras)/metabolism ; Proto-Oncogene Proteins c-myc/*antagonists & inhibitors/*genetics/metabolism ; Skin/cytology/metabolism/pathology ; Testis/cytology/metabolism/pathology ; Transgenes/genetics
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    Cancer: Entangled pathways (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-09-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bernards, Rene -- England -- Nature. 2008 Sep 25;455(7212):479-80. doi: 10.1038/455479a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18818647" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Colorectal Neoplasms/genetics/*metabolism/pathology ; Cyclin-Dependent Kinase 8 ; Cyclin-Dependent Kinases/*metabolism ; Drosophila/genetics/metabolism ; E2F1 Transcription Factor/*metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Retinoblastoma Protein/*metabolism ; Signal Transduction ; Wnt Proteins/metabolism ; beta Catenin/*metabolism
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    Neuroscience: fragile dopamine (2008)
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    Publication Date: 2008-10-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Weinshenker, David -- Warren, Stephen T -- England -- Nature. 2008 Oct 2;455(7213):607-8. doi: 10.1038/455607a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18833269" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dopamine/*metabolism ; Fragile X Mental Retardation Protein/genetics/*metabolism ; Fragile X Syndrome/genetics/*metabolism/physiopathology ; G-Protein-Coupled Receptor Kinase 2/metabolism ; Gene Deletion ; Humans ; Mice ; Signal Transduction
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    Regulation of progenitor cell proliferation and granulocyte function by microRNA-223 (2008)
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    Publication Date: 2008-02-19
    Description: MicroRNAs are abundant in animal genomes and have been predicted to have important roles in a broad range of gene expression programmes. Despite this prominence, there is a dearth of functional knowledge regarding individual mammalian microRNAs. Using a loss-of-function allele in mice, we report here that the myeloid-specific microRNA-223 (miR-223) negatively regulates progenitor proliferation and granulocyte differentiation and activation. miR-223 (also called Mirn223) mutant mice have an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte progenitors. We show that Mef2c, a transcription factor that promotes myeloid progenitor proliferation, is a target of miR-223, and that genetic ablation of Mef2c suppresses progenitor expansion and corrects the neutrophilic phenotype in miR-223 null mice. In addition, granulocytes lacking miR-223 are hypermature, hypersensitive to activating stimuli and display increased fungicidal activity. As a consequence of this neutrophil hyperactivity, miR-223 mutant mice spontaneously develop inflammatory lung pathology and exhibit exaggerated tissue destruction after endotoxin challenge. Our data support a model in which miR-223 acts as a fine-tuner of granulocyte production and the inflammatory response.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Johnnidis, Jonathan B -- Harris, Marian H -- Wheeler, Robert T -- Stehling-Sun, Sandra -- Lam, Michael H -- Kirak, Oktay -- Brummelkamp, Thijn R -- Fleming, Mark D -- Camargo, Fernando D -- England -- Nature. 2008 Feb 28;451(7182):1125-9. doi: 10.1038/nature06607. Epub 2008 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18278031" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Cell Differentiation ; *Cell Proliferation ; Gene Deletion ; Granulocytes/*cytology/immunology/pathology/*physiology ; Inflammation/genetics/immunology/pathology ; Lung/pathology ; MEF2 Transcription Factors ; Mice ; Mice, Knockout ; MicroRNAs/*genetics/*metabolism ; Myogenic Regulatory Factors/genetics/metabolism ; Neutrophils/physiology ; Phenotype ; Stem Cells/*cytology
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    Genetic evidence that FGFs have an instructive role in limb proximal-distal patterning (2008)
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    Publication Date: 2008-05-02
    Description: Half a century ago, the apical ectodermal ridge (AER) at the distal tip of the tetrapod limb bud was shown to produce signals necessary for development along the proximal-distal (P-D) axis, but how these signals influence limb patterning is still much debated. Fibroblast growth factor (FGF) gene family members are key AER-derived signals, with Fgf4, Fgf8, Fgf9 and Fgf17 expressed specifically in the mouse AER. Here we demonstrate that mouse limbs lacking Fgf4, Fgf9 and Fgf17 have normal skeletal pattern, indicating that Fgf8 is sufficient among AER-FGFs to sustain normal limb formation. Inactivation of Fgf8 alone causes a mild skeletal phenotype; however, when we also removed different combinations of the other AER-FGF genes, we obtained unexpected skeletal phenotypes of increasing severity, reflecting the contribution that each FGF can make to the total AER-FGF signal. Analysis of the compound mutant limb buds revealed that, in addition to sustaining cell survival, AER-FGFs regulate P-D-patterning gene expression during early limb bud development, providing genetic evidence that AER-FGFs function to specify a distal domain and challenging the long-standing hypothesis that AER-FGF signalling is permissive rather than instructive for limb patterning. We discuss how a two-signal model for P-D patterning can be integrated with the concept of early specification to explain the genetic data presented here.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2631409/" 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/PMC2631409/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mariani, Francesca V -- Ahn, Christina P -- Martin, Gail R -- F32 HD008696/HD/NICHD NIH HHS/ -- F32 HD008696-01/HD/NICHD NIH HHS/ -- F32 HD008696-02/HD/NICHD NIH HHS/ -- F32 HD008696-03/HD/NICHD NIH HHS/ -- R01 HD034380/HD/NICHD NIH HHS/ -- R01 HD034380-05/HD/NICHD NIH HHS/ -- R01 HD034380-06/HD/NICHD NIH HHS/ -- R01 HD034380-07/HD/NICHD NIH HHS/ -- R01 HD034380-08/HD/NICHD NIH HHS/ -- R01 HD034380-09/HD/NICHD NIH HHS/ -- R01 HD34380/HD/NICHD NIH HHS/ -- England -- Nature. 2008 May 15;453(7193):401-5. doi: 10.1038/nature06876. Epub 2008 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Anatomy and Program in Developmental Biology, School of Medicine, University of California at San Francisco, San Francisco, California 94158-2324, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18449196" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Body Patterning/*genetics/*physiology ; Bone and Bones/embryology/metabolism ; Cell Survival ; Female ; Fibroblast Growth Factor 8/deficiency/genetics/*metabolism ; Fibroblast Growth Factors/deficiency/genetics/*metabolism ; Homeodomain Proteins/genetics ; Limb Buds/cytology/*embryology/metabolism ; Male ; Mice ; Neoplasm Proteins/genetics ; Organ Size ; Signal Transduction
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    Innate immunity and intestinal microbiota in the development of Type 1 diabetes (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-09-23
    Description: Type 1 diabetes (T1D) is a debilitating autoimmune disease that results from T-cell-mediated destruction of insulin-producing beta-cells. Its incidence has increased during the past several decades in developed countries, suggesting that changes in the environment (including the human microbial environment) may influence disease pathogenesis. The incidence of spontaneous T1D in non-obese diabetic (NOD) mice can be affected by the microbial environment in the animal housing facility or by exposure to microbial stimuli, such as injection with mycobacteria or various microbial products. Here we show that specific pathogen-free NOD mice lacking MyD88 protein (an adaptor for multiple innate immune receptors that recognize microbial stimuli) do not develop T1D. The effect is dependent on commensal microbes because germ-free MyD88-negative NOD mice develop robust diabetes, whereas colonization of these germ-free MyD88-negative NOD mice with a defined microbial consortium (representing bacterial phyla normally present in human gut) attenuates T1D. We also find that MyD88 deficiency changes the composition of the distal gut microbiota, and that exposure to the microbiota of specific pathogen-free MyD88-negative NOD donors attenuates T1D in germ-free NOD recipients. Together, these findings indicate that interaction of the intestinal microbes with the innate immune system is a critical epigenetic factor modifying T1D predisposition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2574766/" 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/PMC2574766/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wen, Li -- Ley, Ruth E -- Volchkov, Pavel Yu -- Stranges, Peter B -- Avanesyan, Lia -- Stonebraker, Austin C -- Hu, Changyun -- Wong, F Susan -- Szot, Gregory L -- Bluestone, Jeffrey A -- Gordon, Jeffrey I -- Chervonsky, Alexander V -- DK063452/DK/NIDDK NIH HHS/ -- DK30292/DK/NIDDK NIH HHS/ -- DK42086/DK/NIDDK NIH HHS/ -- DK45735/DK/NIDDK NIH HHS/ -- DK70977/DK/NIDDK NIH HHS/ -- P30 DK042086/DK/NIDDK NIH HHS/ -- P30 DK042086-16/DK/NIDDK NIH HHS/ -- P30 DK045735/DK/NIDDK NIH HHS/ -- P30 DK045735-10/DK/NIDDK NIH HHS/ -- P30 DK045735-119006/DK/NIDDK NIH HHS/ -- P30 DK056341/DK/NIDDK NIH HHS/ -- P30 DK056341-07/DK/NIDDK NIH HHS/ -- P30 DK056341-08/DK/NIDDK NIH HHS/ -- P30 DK063720/DK/NIDDK NIH HHS/ -- P30 DK063720-01/DK/NIDDK NIH HHS/ -- P30 DK63720/DK/NIDDK NIH HHS/ -- R01 DK030292/DK/NIDDK NIH HHS/ -- R01 DK030292-24/DK/NIDDK NIH HHS/ -- R01 DK070977/DK/NIDDK NIH HHS/ -- R01 DK070977-04/DK/NIDDK NIH HHS/ -- R21 DK063452/DK/NIDDK NIH HHS/ -- R21 DK063452-02/DK/NIDDK NIH HHS/ -- R37 AI046643/AI/NIAID NIH HHS/ -- R37 AI046643-10/AI/NIAID NIH HHS/ -- R37 AI46643/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Oct 23;455(7216):1109-13. doi: 10.1038/nature07336. Epub 2008 Sep 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Endocrinology, 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/18806780" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacteria/classification/genetics/*immunology/isolation & purification ; CD8-Positive T-Lymphocytes/immunology ; Diabetes Mellitus, Type 1/genetics/*immunology/*microbiology ; Female ; Immunity, Innate/genetics/*immunology ; Interferon-gamma/immunology ; Intestines/*microbiology ; Islets of Langerhans/pathology ; Male ; Mice ; Mice, Inbred NOD ; Mice, Knockout ; Mice, SCID ; Molecular Sequence Data ; Myeloid Differentiation Factor 88/genetics ; Phylogeny ; Specific Pathogen-Free Organisms ; Time Factors
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    Virology: the battle within (2008)
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    Publication Date: 2008-01-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wenner, Melinda -- England -- Nature. 2008 Jan 24;451(7177):388-9. doi: 10.1038/451388a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18216825" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Endogenous Retroviruses/genetics/immunology ; Genetic Complementation Test ; HIV Infections/*complications/immunology/virology ; HIV-1/immunology/pathogenicity/*physiology ; Herpesvirus 6, Human/pathogenicity/*physiology ; Herpesvirus 7, Human/physiology ; Host-Pathogen Interactions ; Humans ; Mice ; Models, Immunological ; Palatine Tonsil/immunology/virology ; Roseolovirus Infections/*complications/immunology/virology ; Superinfection/*immunology/microbiology/prevention & control/*virology ; Tissue Culture Techniques ; Virus Replication
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    Cohesin mediates transcriptional insulation by CCCTC-binding factor (2008)
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    Publication Date: 2008-02-01
    Description: Cohesin complexes mediate sister-chromatid cohesion in dividing cells but may also contribute to gene regulation in postmitotic cells. How cohesin regulates gene expression is not known. Here we describe cohesin-binding sites in the human genome and show that most of these are associated with the CCCTC-binding factor (CTCF), a zinc-finger protein required for transcriptional insulation. CTCF is dispensable for cohesin loading onto DNA, but is needed to enrich cohesin at specific binding sites. Cohesin enables CTCF to insulate promoters from distant enhancers and controls transcription at the H19/IGF2 (insulin-like growth factor 2) locus. This role of cohesin seems to be independent of its role in cohesion. We propose that cohesin functions as a transcriptional insulator, and speculate that subtle deficiencies in this function contribute to 'cohesinopathies' such as Cornelia de Lange syndrome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wendt, Kerstin S -- Yoshida, Keisuke -- Itoh, Takehiko -- Bando, Masashige -- Koch, Birgit -- Schirghuber, Erika -- Tsutsumi, Shuichi -- Nagae, Genta -- Ishihara, Ko -- Mishiro, Tsuyoshi -- Yahata, Kazuhide -- Imamoto, Fumio -- Aburatani, Hiroyuki -- Nakao, Mitsuyoshi -- Imamoto, Naoko -- Maeshima, Kazuhiro -- Shirahige, Katsuhiko -- Peters, Jan-Michael -- England -- Nature. 2008 Feb 14;451(7180):796-801. doi: 10.1038/nature06634. Epub 2008 Jan 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology, Dr. Bohr Gasse 7, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18235444" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Brain/cytology/metabolism ; Cell Cycle Proteins/*metabolism ; Cell Differentiation ; Chromosomal Proteins, Non-Histone/*metabolism ; Consensus Sequence/genetics ; DNA/genetics/metabolism ; DNA-Binding Proteins/*metabolism ; Enhancer Elements, Genetic/genetics ; Female ; Gene Expression Regulation/*genetics ; Genome, Human/genetics ; HeLa Cells ; Humans ; Insulin-Like Growth Factor II/genetics ; Mice ; Mitosis ; Mothers ; Nuclear Proteins/*metabolism ; Promoter Regions, Genetic/genetics ; RNA, Long Noncoding ; RNA, Untranslated/genetics ; Repressor Proteins/*metabolism ; Transcription, Genetic/*genetics
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    Immunology: Surprising side effects (2008)
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    Publication Date: 2008-08-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bevan, Michael J -- Fink, Pamela J -- England -- Nature. 2008 Aug 14;454(7206):837-8. doi: 10.1038/454837a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18704076" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Fingolimod Hydrochloride ; Immunosuppressive Agents/*pharmacology ; Lymph Nodes/*drug effects/immunology ; Lymphocytes/drug effects/immunology/virology ; Lymphocytic Choriomeningitis/drug therapy/*immunology ; Lymphocytic choriomeningitis virus/immunology ; Mice ; Propylene Glycols/*pharmacology ; Sphingosine/*analogs & derivatives/pharmacology
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    SCFbeta-TRCP controls oncogenic transformation and neural differentiation through REST degradation (2008)
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    Publication Date: 2008-03-21
    Description: The RE1-silencing transcription factor (REST, also known as NRSF) is a master repressor of neuronal gene expression and neuronal programmes in non-neuronal lineages. Recently, REST was identified as a human tumour suppressor in epithelial tissues, suggesting that its regulation may have important physiological and pathological consequences. However, the pathways controlling REST have yet to be elucidated. Here we show that REST is regulated by ubiquitin-mediated proteolysis, and use an RNA interference (RNAi) screen to identify a Skp1-Cul1-F-box protein complex containing the F-box protein beta-TRCP (SCF(beta-TRCP)) as an E3 ubiquitin ligase responsible for REST degradation. beta-TRCP binds and ubiquitinates REST and controls its stability through a conserved phospho-degron. During neural differentiation, REST is degraded in a beta-TRCP-dependent manner. beta-TRCP is required for proper neural differentiation only in the presence of REST, indicating that beta-TRCP facilitates this process through degradation of REST. Conversely, failure to degrade REST attenuates differentiation. Furthermore, we find that beta-TRCP overexpression, which is common in human epithelial cancers, causes oncogenic transformation of human mammary epithelial cells and that this pathogenic function requires REST degradation. Thus, REST is a key target in beta-TRCP-driven transformation and the beta-TRCP-REST axis is a new regulatory pathway controlling neurogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2688689/" 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/PMC2688689/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Westbrook, Thomas F -- Hu, Guang -- Ang, Xiaolu L -- Mulligan, Peter -- Pavlova, Natalya N -- Liang, Anthony -- Leng, Yumei -- Maehr, Rene -- Shi, Yang -- Harper, J Wade -- Elledge, Stephen J -- F31 NS054507-01/NS/NINDS NIH HHS/ -- R01 AG011085/AG/NIA NIH HHS/ -- R01 AG011085-16/AG/NIA NIH HHS/ -- R01 GM054137/GM/NIGMS NIH HHS/ -- R01 GM054137-13/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 20;452(7185):370-4. doi: 10.1038/nature06780.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Genetics, Harvard Partners Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18354483" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cell Line, Tumor ; *Cell Transformation, Neoplastic ; Conserved Sequence ; Humans ; Mice ; Neurons/*cytology/*pathology ; Phosphorylation ; Protein Processing, Post-Translational ; RNA Interference ; Repressor Proteins/genetics/*metabolism ; SKP Cullin F-Box Protein Ligases/*metabolism ; Substrate Specificity ; Transcription Factors/genetics/*metabolism ; Ubiquitin/metabolism ; beta-Transducin Repeat-Containing Proteins/genetics/*metabolism
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    SAP-controlled T-B cell interactions underlie germinal centre formation (2008)
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    Publication Date: 2008-10-10
    Description: Generation of long-term antibody-mediated immunity depends on the germinal centre reaction, which requires cooperation between antigen-specific T and B lymphocytes. In human X-linked lymphoproliferative disease and its gene-targeted mouse model, loss-of-function mutations in signalling lymphocyte activation molecule-associated protein (SAP, encoded by SH2D1a) cause a profound defect in germinal centre formation by an as yet unknown mechanism. Here, using two-photon intravital imaging, we show that SAP deficiency selectively impairs the ability of CD4(+) T cells to stably interact with cognate B cells but not antigen-presenting dendritic cells. This selective defect results in a failure of antigen-specific B cells to receive adequate levels of contact-dependent T-cell help to expand normally, despite Sap(-/-) T cells exhibiting the known characteristics of otherwise competent helper T cells. Furthermore, the lack of stable interactions with B cells renders Sap(-/-) T cells unable to be efficiently recruited to and retained in a nascent germinal centre to sustain the germinal centre reaction. These results offer an explanation for the germinal centre defect due to SAP deficiency and provide new insights into the bi-directional communication between cognate T and B cells in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2652134/" 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/PMC2652134/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qi, Hai -- Cannons, Jennifer L -- Klauschen, Frederick -- Schwartzberg, Pamela L -- Germain, Ronald N -- Z01 AI000545-19/Intramural NIH HHS/ -- England -- Nature. 2008 Oct 9;455(7214):764-9. doi: 10.1038/nature07345.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18843362" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*cytology/*immunology ; CD4-Positive T-Lymphocytes/*cytology/*immunology ; Cell Adhesion ; Cell Communication ; Cells, Cultured ; Chimera/immunology ; Dendritic Cells/immunology ; Germinal Center/*cytology/*immunology ; Intracellular Signaling Peptides and Proteins/deficiency/genetics/*metabolism ; Lymphocyte Activation ; Mice
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    Neuroscience: State-sanctioned synchrony (2008)
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    Publication Date: 2008-08-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cruikshank, Scott J -- Connors, Barry W -- P50 MH086400/MH/NIMH NIH HHS/ -- R01 NS025983/NS/NINDS NIH HHS/ -- England -- Nature. 2008 Aug 14;454(7206):839-40. doi: 10.1038/454839a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18704078" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cerebral Cortex/*physiology ; Electroencephalography ; Membrane Potentials/physiology ; Mice ; Neurons/*physiology ; Wakefulness/*physiology
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    Prolyl 4-hydroxylation regulates Argonaute 2 stability (2008)
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    Publication Date: 2008-08-12
    Description: Human Argonaute (Ago) proteins are essential components of the RNA-induced silencing complexes (RISCs). Argonaute 2 (Ago2) has a P-element-induced wimpy testis (PIWI) domain, which folds like RNase H and is responsible for target RNA cleavage in RNA interference. Proteins such as Dicer, TRBP, MOV10, RHA, RCK/p54 and KIAA1093 associate with Ago proteins and participate in small RNA processing, RISC loading and localization of Ago proteins in the cytoplasmic messenger RNA processing bodies. However, mechanisms that regulate RNA interference remain obscure. Here we report physical interactions between Ago2 and the alpha-(P4H-alpha(I)) and beta-(P4H-beta) subunits of the type I collagen prolyl-4-hydroxylase (C-P4H(I)). Mass spectrometric analysis identified hydroxylation of the endogenous Ago2 at proline 700. In vitro, both Ago2 and Ago4 seem to be more efficiently hydroxylated than Ago1 and Ago3 by recombinant human C-P4H(I). Importantly, human cells depleted of P4H-alpha(I) or P4H-beta by short hairpin RNA and P4H-alpha(I) null mouse embryonic fibroblast cells showed reduced stability of Ago2 and impaired short interfering RNA programmed RISC activity. Furthermore, mutation of proline 700 to alanine also resulted in destabilization of Ago2, thus linking Ago2 P700 and hydroxylation at this residue to its stability regulation. These findings identify hydroxylation as a post-translational modification important for Ago2 stability and effective RNA interference.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661850/" 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/PMC2661850/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qi, Hank H -- Ongusaha, Pat P -- Myllyharju, Johanna -- Cheng, Dongmei -- Pakkanen, Outi -- Shi, Yujiang -- Lee, Sam W -- Peng, Junmin -- Shi, Yang -- AG025688/AG/NIA NIH HHS/ -- GM53874/GM/NIGMS NIH HHS/ -- R01 GM053874/GM/NIGMS NIH HHS/ -- R01 GM053874-15/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Sep 18;455(7211):421-4. doi: 10.1038/nature07186. Epub 2008 Aug 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Harvard Medical School, New Research Building 854, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18690212" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins ; Enzyme Stability ; Eukaryotic Initiation Factor-2/*chemistry/genetics/*metabolism ; HeLa Cells ; Humans ; Hydroxylation ; Mice ; MicroRNAs/genetics ; Proline/*metabolism ; Protein Binding ; Protein Subunits ; RNA-Induced Silencing Complex/genetics/metabolism
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    Cancer: Hedgehog's other great trick (2008)
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    Publication Date: 2008-09-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Curran, Tom -- Ng, Jessica M Y -- England -- Nature. 2008 Sep 18;455(7211):293-4. doi: 10.1038/455293a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18800119" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Hedgehog Proteins/*metabolism ; Humans ; Mice ; Neoplasm Transplantation ; Neoplasms/*metabolism/pathology ; Paracrine Communication/*physiology ; Receptors, G-Protein-Coupled/antagonists & inhibitors/metabolism ; Stromal Cells/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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    Listeriolysin O allows Listeria monocytogenes replication in macrophage vacuoles (2008)
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    Publication Date: 2008-01-19
    Description: Listeria monocytogenes is an intracellular bacterial pathogen that replicates rapidly in the cytosol of host cells during acute infection. Surprisingly, these bacteria were found to occupy vacuoles in liver granuloma macrophages during persistent infection of severe combined immunodeficient (SCID) mice. Here we show that L. monocytogenes can replicate in vacuoles within macrophages. In livers of SCID mice infected for 21 days, we observed bacteria in large LAMP1(+) compartments that we termed spacious Listeria-containing phagosomes (SLAPs). SLAPs were also observed in vitro, and were found to be non-acidic and non-degradative compartments that are generated in an autophagy-dependent manner. The replication rate of bacteria in SLAPs was found to be reduced compared to the rate of those in the cytosol. Listeriolysin O (LLO, encoded by hly), a pore-forming toxin essential for L. monocytogenes virulence, was necessary and sufficient for SLAP formation. A L. monocytogenes mutant with low LLO expression was impaired for phagosome escape but replicated slowly in SLAPs over a 72 h period. Therefore, our studies reveal a role for LLO in promoting L. monocytogenes replication in vacuoles and suggest a mechanism by which this pathogen can establish persistent infection in host macrophages.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Birmingham, Cheryl L -- Canadien, Veronica -- Kaniuk, Natalia A -- Steinberg, Benjamin E -- Higgins, Darren E -- Brumell, John H -- England -- Nature. 2008 Jan 17;451(7176):350-4. doi: 10.1038/nature06479.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Biology Program, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18202661" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy ; Bacterial Toxins/genetics/*metabolism ; Chronic Disease ; Heat-Shock Proteins/genetics/*metabolism ; Hemolysin Proteins/genetics/*metabolism ; Listeria monocytogenes/*growth & development/metabolism/*pathogenicity ; Listeriosis/microbiology/pathology ; Liver/microbiology ; Lysosome-Associated Membrane Glycoproteins/metabolism ; Macrophages/*cytology/*microbiology ; Mice ; Mice, SCID ; Phagosomes/metabolism/microbiology ; Vacuoles/metabolism/*microbiology ; Virulence
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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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    Japan fast-tracks stem-cell patent (2008)
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    Publication Date: 2008-09-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cyranoski, David -- England -- Nature. 2008 Sep 18;455(7211):269. doi: 10.1038/455269b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18800093" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/physiology ; Animals ; Humans ; Internationality ; Japan ; Mice ; Patents as Topic/*legislation & jurisprudence ; *Pluripotent Stem Cells/cytology ; Time Factors ; United States ; Universities
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    A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility (2008)
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    Publication Date: 2008-11-21
    Description: The kidney has an important role in the regulation of acid-base homeostasis. Renal ammonium production and excretion are essential for net acid excretion under basal conditions and during metabolic acidosis. Ammonium is secreted into the urine by the collecting duct, a distal nephron segment where ammonium transport is believed to occur by non-ionic NH(3) diffusion coupled to H(+) secretion. Here we show that this process is largely dependent on the Rhesus factor Rhcg. Mice lacking Rhcg have abnormal urinary acidification due to impaired ammonium excretion on acid loading-a feature of distal renal tubular acidosis. In vitro microperfused collecting ducts of Rhcg(-/-) acid-loaded mice show reduced apical permeability to NH(3) and impaired transepithelial NH(3) transport. Furthermore, Rhcg is localized in epididymal epithelial cells and is required for normal fertility and epididymal fluid pH. We anticipate a critical role for Rhcg in ammonium handling and pH homeostasis both in the kidney and the male reproductive tract.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Biver, Sophie -- Belge, Hendrica -- Bourgeois, Soline -- Van Vooren, Pascale -- Nowik, Marta -- Scohy, Sophie -- Houillier, Pascal -- Szpirer, Josiane -- Szpirer, Claude -- Wagner, Carsten A -- Devuyst, Olivier -- Marini, Anna Maria -- England -- Nature. 2008 Nov 20;456(7220):339-43. doi: 10.1038/nature07518.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Libre de Bruxelles (U.L.B.), Institut de Biologie et de Medecine Moleculaires, Laboratoire de Biologie du Developpement, Gosselies, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19020613" target="_blank"〉PubMed〈/a〉
    Keywords: Acidosis/physiopathology ; Acids/metabolism ; Animals ; Biological Transport ; Body Fluids ; Cation Transport Proteins/deficiency/genetics/*metabolism ; Epithelial Cells/metabolism ; Fertility/*physiology ; Gene Deletion ; Genitalia, Male/cytology/metabolism ; Homeostasis ; Hydrogen-Ion Concentration ; Kidney/*physiology ; Kidney Tubules, Collecting/physiology ; Kidney Tubules, Distal/physiology ; Male ; Membrane Glycoproteins/deficiency/genetics/*metabolism ; Mice ; Permeability ; Quaternary Ammonium Compounds/*urine ; Stress, Physiological ; Weight Loss
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    RNA interference: generic block on angiogenesis (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-04-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kalluri, Raghu -- Kanasaki, Keizo -- England -- Nature. 2008 Apr 3;452(7187):543-5. doi: 10.1038/452543a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18385725" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Humans ; Immunity, Innate/immunology ; Interferon-gamma/immunology ; Interleukin-12/immunology ; Macular Degeneration/complications/genetics/therapy ; Mice ; Neovascularization, Pathologic/genetics/*immunology/*prevention & control/therapy ; RNA, Small Interfering/genetics/*immunology/*metabolism ; Toll-Like Receptor 3/deficiency/genetics/*metabolism ; Vascular Endothelial Growth Factor A/genetics
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    A discontinuous hammerhead ribozyme embedded in a mammalian messenger RNA (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-07-11
    Description: Structured RNAs embedded in the untranslated regions (UTRs) of messenger RNAs can regulate gene expression. In bacteria, control of a metabolite gene is mediated by the self-cleaving activity of a ribozyme embedded in its 5' UTR. This discovery has raised the question of whether gene-regulating ribozymes also exist in eukaryotic mRNAs. Here we show that highly active hammerhead ribozymes are present in the 3' UTRs of rodent C-type lectin type II (Clec2) genes. Using a hammerhead RNA motif search with relaxed delimitation of the non-conserved regions, we detected ribozyme sequences in which the invariant regions, in contrast to the previously identified continuous hammerheads, occur as two fragments separated by hundreds of nucleotides. Notably, a fragment pair can assemble to form an active hammerhead ribozyme structure between the translation termination and the polyadenylation signals within the 3' UTR. We demonstrate that this hammerhead structure can self-cleave both in vitro and in vivo, and is able to reduce protein expression in mouse cells. These results indicate that an unrecognized mechanism of post-transcriptional gene regulation involving association of discontinuous ribozyme sequences within an mRNA may be modulating the expression of several CLEC2 proteins that function in bone remodelling and the immune response of several mammals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612532/" 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/PMC2612532/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martick, Monika -- Horan, Lucas H -- Noller, Harry F -- Scott, William G -- R01 AI043393/AI/NIAID NIH HHS/ -- R01 AI043393-09/AI/NIAID NIH HHS/ -- R01 GM087721/GM/NIGMS NIH HHS/ -- R01043393/PHS HHS/ -- England -- Nature. 2008 Aug 14;454(7206):899-902. doi: 10.1038/nature07117. Epub 2008 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Molecular Biology of RNA, University of California, Santa Cruz, California 95064, USA. mmartick@yahoo.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18615019" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/genetics ; Animals ; Down-Regulation ; Lectins, C-Type/genetics/metabolism ; Mice ; Models, Molecular ; NIH 3T3 Cells ; Nucleic Acid Conformation ; RNA, Catalytic/chemistry/*genetics/metabolism ; RNA, Messenger/chemistry/*genetics/metabolism ; Rats ; Reverse Transcriptase Polymerase Chain Reaction
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    Japan ramps up patent effort to keep iPS lead (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-06-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cyranoski, David -- England -- Nature. 2008 Jun 19;453(7198):962-3. doi: 10.1038/453962a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18563108" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Embryonic Stem Cells/cytology ; Humans ; Japan ; Mice ; *Patents as Topic/legislation & jurisprudence ; *Pluripotent Stem Cells/cytology ; United States
    Print ISSN: 0028-0836
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    Efficient tumour formation by single human melanoma cells (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-12-05
    Description: A fundamental question in cancer biology is whether cells with tumorigenic potential are common or rare within human cancers. Studies on diverse cancers, including melanoma, have indicated that only rare human cancer cells (0.1-0.0001%) form tumours when transplanted into non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice. However, the extent to which NOD/SCID mice underestimate the frequency of tumorigenic human cancer cells has been uncertain. Here we show that modified xenotransplantation assay conditions, including the use of more highly immunocompromised NOD/SCID interleukin-2 receptor gamma chain null (Il2rg(-/-)) mice, can increase the detection of tumorigenic melanoma cells by several orders of magnitude. In limiting dilution assays, approximately 25% of unselected melanoma cells from 12 different patients, including cells from primary and metastatic melanomas obtained directly from patients, formed tumours under these more permissive conditions. In single-cell transplants, an average of 27% of unselected melanoma cells from four different patients formed tumours. Modifications to xenotransplantation assays can therefore dramatically increase the detectable frequency of tumorigenic cells, demonstrating that they are common in some human cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2597380/" 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/PMC2597380/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Quintana, Elsa -- Shackleton, Mark -- Sabel, Michael S -- Fullen, Douglas R -- Johnson, Timothy M -- Morrison, Sean J -- 5P60-DK20572/DK/NIDDK NIH HHS/ -- CA46592/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Dec 4;456(7222):593-8. doi: 10.1038/nature07567.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Life Sciences Institute, Department of Internal Medicine, and Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052619" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Count ; Humans ; Interleukin Receptor Common gamma Subunit/deficiency/genetics ; Melanoma/*pathology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; *Neoplasm Transplantation ; Neoplastic Stem Cells/pathology ; *Transplantation, Heterologous
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    Regenerative medicine: short cut to cell replacement (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-10-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blelloch, Robert -- K08 NS048118/NS/NINDS NIH HHS/ -- K08 NS048118-04/NS/NINDS NIH HHS/ -- R01 NS057221/NS/NINDS NIH HHS/ -- R01 NS057221-02/NS/NINDS NIH HHS/ -- England -- Nature. 2008 Oct 2;455(7213):604-5. doi: 10.1038/455604a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18833266" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism ; Cell Shape ; Cell Size ; *Cell Transdifferentiation ; Homeodomain Proteins/genetics/metabolism ; Insulin-Secreting Cells/*cytology/metabolism ; Maf Transcription Factors, Large/genetics/metabolism ; Mice ; Nerve Tissue Proteins/genetics/metabolism ; Pancreas, Exocrine/*cytology/embryology/secretion ; Regenerative Medicine/*methods ; Trans-Activators/genetics/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-05-13
    Description: Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kanasaki, Keizo -- Palmsten, Kristin -- Sugimoto, Hikaru -- Ahmad, Shakil -- Hamano, Yuki -- Xie, Liang -- Parry, Samuel -- Augustin, Hellmut G -- Gattone, Vincent H -- Folkman, Judah -- Strauss, Jerome F -- Kalluri, Raghu -- DK 13193/DK/NIDDK NIH HHS/ -- DK 55001/DK/NIDDK NIH HHS/ -- DK 61688/DK/NIDDK NIH HHS/ -- DK 62987/DK/NIDDK NIH HHS/ -- G0700288/Medical Research Council/United Kingdom -- R01 DK055001/DK/NIDDK NIH HHS/ -- R01 DK061688/DK/NIDDK NIH HHS/ -- British Heart Foundation/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2008 Jun 19;453(7198):1117-21. doi: 10.1038/nature06951. Epub 2008 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18469803" target="_blank"〉PubMed〈/a〉
    Keywords: Albumins/analysis ; Animals ; Anoxia/metabolism ; Blood Pressure ; Catechol O-Methyltransferase/analysis/*deficiency/genetics ; Creatinine/urine ; Disease Models, Animal ; Estradiol/*analogs & derivatives/blood/*deficiency/urine ; Female ; Humans ; Hypertension ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Killer Cells, Natural/immunology ; Litter Size ; Male ; Mice ; Placenta/enzymology/pathology ; Pre-Eclampsia/blood/enzymology/*metabolism/urine ; Pregnancy ; Proteinuria ; Vascular Endothelial Growth Factor Receptor-1/blood
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    Control of T(reg) and T(H)17 cell differentiation by the aryl hydrocarbon receptor (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-03-26
    Description: Regulatory T cells (T(reg)) expressing the transcription factor Foxp3 control the autoreactive components of the immune system. The development of T(reg) cells is reciprocally related to that of pro-inflammatory T cells producing interleukin-17 (T(H)17). Although T(reg) cell dysfunction and/or T(H)17 cell dysregulation are thought to contribute to the development of autoimmune disorders, little is known about the physiological pathways that control the generation of these cell lineages. Here we report the identification of the ligand-activated transcription factor aryl hydrocarbon receptor (AHR) as a regulator of T(reg) and T(H)17 cell differentiation in mice. AHR activation by its ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin induced functional T(reg) cells that suppressed experimental autoimmune encephalomyelitis. On the other hand, AHR activation by 6-formylindolo[3,2-b]carbazole interfered with T(reg) cell development, boosted T(H)17 cell differentiation and increased the severity of experimental autoimmune encephalomyelitis in mice. Thus, AHR regulates both T(reg) and T(H)17 cell differentiation in a ligand-specific fashion, constituting a unique target for therapeutic immunomodulation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Quintana, Francisco J -- Basso, Alexandre S -- Iglesias, Antonio H -- Korn, Thomas -- Farez, Mauricio F -- Bettelli, Estelle -- Caccamo, Mario -- Oukka, Mohamed -- Weiner, Howard L -- AI435801/AI/NIAID NIH HHS/ -- NS38037/NS/NINDS NIH HHS/ -- P01 NS038037/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 NS059996/NS/NINDS NIH HHS/ -- R01AI073542-01/AI/NIAID NIH HHS/ -- England -- Nature. 2008 May 1;453(7191):65-71. doi: 10.1038/nature06880. Epub 2008 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18362915" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carbazoles/metabolism/pharmacology ; *Cell Differentiation ; Encephalomyelitis, Autoimmune, Experimental/chemically induced/immunology ; Forkhead Transcription Factors/genetics/metabolism ; Humans ; Indoles/metabolism/pharmacology ; Interleukin-17/*metabolism ; Ligands ; Mice ; Mice, Inbred C57BL ; Receptors, Aryl Hydrocarbon/genetics/*metabolism ; T-Lymphocytes, Helper-Inducer/*cytology/drug effects/*metabolism ; T-Lymphocytes, Regulatory/*cytology/drug effects/*metabolism ; Tetrachlorodibenzodioxin/metabolism/pharmacology ; Transforming Growth Factor beta1/immunology/metabolism
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    Neuropathology: Alzheimer's in real time (2008)
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    Publication Date: 2008-02-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Masliah, Eliezer -- England -- Nature. 2008 Feb 7;451(7179):638-9. doi: 10.1038/451638a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18256653" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/*metabolism/*pathology ; Amyloid beta-Peptides/*metabolism/toxicity ; Animals ; Axons/metabolism ; Dendrites/metabolism ; Disease Models, Animal ; Disease Progression ; Humans ; Mice ; Microglia/metabolism ; Plaque, Amyloid/*metabolism/*pathology ; Time Factors
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    Stem cells: 5 things to know before jumping on the iPS bandwagon (2008)
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    Publication Date: 2008-03-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cyranoski, David -- England -- Nature. 2008 Mar 27;452(7186):406-8. doi: 10.1038/452406a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18368095" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; Cell Culture Techniques ; Cell Differentiation ; Cell- and Tissue-Based Therapy/ethics/trends ; Embryonic Stem Cells/cytology/transplantation ; Female ; Humans ; Male ; Mice ; Pluripotent Stem Cells/*cytology/transplantation ; Reproductive Techniques, Assisted/ethics/trends ; Research Embryo Creation/ethics/legislation & jurisprudence ; Skin/cytology ; Transduction, Genetic/methods/standards
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    Secreted transcription factor controls Mycobacterium tuberculosis virulence (2008)
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    Publication Date: 2008-08-08
    Description: Bacterial pathogens trigger specialized virulence factor secretion systems on encountering host cells. The ESX-1 protein secretion system of Mycobacterium tuberculosis-the causative agent of the human disease tuberculosis-delivers bacterial proteins into host cells during infection and is critical for virulence, but how it is regulated is unknown. Here we show that EspR (also known as Rv3849) is a key regulator of ESX-1 that is required for secretion and virulence in mice. EspR activates transcription of an operon that includes three ESX-1 components, Rv3616c-Rv3614c, whose expression in turn promotes secretion of ESX-1 substrates. EspR directly binds to and activates the Rv3616c-Rv3614c promoter and, unexpectedly, is itself secreted from the bacterial cell by the ESX-1 system that it regulates. Efflux of the DNA-binding regulator results in reduced Rv3616c-Rv3614c transcription, and thus reduced ESX-1 secretion. Our results reveal a direct negative feedback loop that regulates the activity of a secretion system essential for virulence. As the virulence factors secreted by the ESX-1 system are highly antigenic, fine control of secretion may be critical to successful infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862998/" 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/PMC2862998/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raghavan, Sridharan -- Manzanillo, Paolo -- Chan, Kaman -- Dovey, Cole -- Cox, Jeffery S -- AI51667/AI/NIAID NIH HHS/ -- AI63302/AI/NIAID NIH HHS/ -- P01 AI063302/AI/NIAID NIH HHS/ -- P01 AI063302-010001/AI/NIAID NIH HHS/ -- P01 AI063302-020001/AI/NIAID NIH HHS/ -- P01 AI063302-030001/AI/NIAID NIH HHS/ -- P01 AI063302-040001/AI/NIAID NIH HHS/ -- P01 AI063302-050001/AI/NIAID NIH HHS/ -- R01 AI051667/AI/NIAID NIH HHS/ -- R01 AI051667-06/AI/NIAID NIH HHS/ -- R01 AI051667-07/AI/NIAID NIH HHS/ -- R01 AI051667-08/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Aug 7;454(7205):717-21. doi: 10.1038/nature07219.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, 600 16th Street, Campus Box 2200, San Francisco, California 94143-2200, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18685700" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacterial Proteins/chemistry/genetics/*metabolism/secretion ; Gene Expression Regulation, Bacterial ; Macrophages/microbiology ; Mice ; Mice, Inbred C57BL ; Mycobacterium tuberculosis/genetics/*pathogenicity ; Operon/genetics ; Promoter Regions, Genetic/genetics ; Transcription Factors/chemistry/*metabolism/*secretion ; Transcription, Genetic ; Transcriptional Activation ; Virulence/genetics ; Virulence Factors/genetics/*metabolism
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    Immunology: blood lines redrawn (2008)
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    Publication Date: 2008-04-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Graf, Thomas -- England -- Nature. 2008 Apr 10;452(7188):702-3. doi: 10.1038/452702a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18401396" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/cytology ; *Cell Lineage ; Dendritic Cells/cytology/metabolism ; Granulocytes/cytology/metabolism ; *Hematopoiesis ; Hematopoietic Stem Cells/*cytology/metabolism ; Macrophages/cytology/metabolism ; Mice ; *Models, Biological ; Myeloid Cells/*cytology/metabolism ; T-Lymphocytes/*cytology/metabolism ; Thymus Gland/*cytology
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    Stem cells: in search of common ground (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-02-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blow, Nathan -- England -- Nature. 2008 Feb 14;451(7180):855-8. doi: 10.1038/451855a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18273022" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Alginates/metabolism ; Animals ; Cell Adhesion ; Cell Culture Techniques/instrumentation/*methods ; Cell Differentiation ; Coculture Techniques ; Embryonic Stem Cells/*cytology ; Glucuronic Acid/metabolism ; Hexuronic Acids/metabolism ; Humans ; Mesenchymal Stromal Cells/cytology ; Mice ; Pluripotent Stem Cells/cytology
    Print ISSN: 0028-0836
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    Immunology: T cells hang in the balance (2008)
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    Publication Date: 2008-05-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stevens, Emily A -- Bradfield, Christopher A -- R01 ES005703/ES/NIEHS NIH HHS/ -- England -- Nature. 2008 May 1;453(7191):46-7. doi: 10.1038/453046a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18451850" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carbazoles/pharmacokinetics/pharmacology ; *Cell Differentiation/drug effects ; Dioxins/pharmacokinetics/pharmacology ; Encephalomyelitis, Autoimmune, Experimental/chemically induced/immunology ; Environmental Pollutants/*pharmacology/toxicity ; Humans ; Indoles/pharmacokinetics/pharmacology ; Interleukin-17/*metabolism ; Mice ; Receptors, Aryl Hydrocarbon/deficiency/*metabolism ; T-Lymphocytes, Helper-Inducer/*cytology/drug effects/immunology/*metabolism ; T-Lymphocytes, Regulatory/*cytology/drug effects/immunology/*metabolism ; Transforming Growth Factor beta/immunology/pharmacology
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    A microbial symbiosis factor prevents intestinal inflammatory disease (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-05-30
    Description: Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mazmanian, Sarkis K -- Round, June L -- Kasper, Dennis L -- R01 AI039576/AI/NIAID NIH HHS/ -- England -- Nature. 2008 May 29;453(7195):620-5. doi: 10.1038/nature07008.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biology, California Institute of Technology, Pasadena, California 91125, USA. sarkis@caltech.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18509436" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacteroides fragilis/genetics/immunology/*physiology ; CD4-Positive T-Lymphocytes/drug effects/immunology/metabolism ; Colitis/chemically induced/immunology/*microbiology/*prevention & control ; Disease Models, Animal ; Germ-Free Life ; Helicobacter hepaticus/*pathogenicity ; Inflammation/chemically induced/microbiology/pathology/prevention & control ; Inflammatory Bowel Diseases/immunology/microbiology/pathology/prevention & ; control ; Interleukin-10/biosynthesis/genetics/metabolism ; Interleukin-17/metabolism ; Intestines/drug effects/immunology/microbiology/pathology ; Mice ; Polysaccharides, Bacterial/genetics/immunology/metabolism/pharmacology ; Symbiosis/*physiology ; Tumor Necrosis Factor-alpha/biosynthesis/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Drug discovery: a lifeline for suffocating tissues (2008)
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    Publication Date: 2008-06-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mazzone, Massimiliano -- Carmeliet, Peter -- England -- Nature. 2008 Jun 26;453(7199):1194-5. doi: 10.1038/4531194a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18580938" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Vessels/cytology/drug effects/growth & development ; Ischemia/*drug therapy/metabolism/pathology ; Mice ; Neovascularization, Physiologic/*drug effects ; Nitric Oxide/adverse effects/metabolism ; Nitrites/metabolism/*pharmacology/*therapeutic use
    Print ISSN: 0028-0836
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    A phosphatase cascade by which rewarding stimuli control nucleosomal response (2008)
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    Publication Date: 2008-05-23
    Description: Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796210/" 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/PMC2796210/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stipanovich, Alexandre -- Valjent, Emmanuel -- Matamales, Miriam -- Nishi, Akinori -- Ahn, Jung-Hyuck -- Maroteaux, Matthieu -- Bertran-Gonzalez, Jesus -- Brami-Cherrier, Karen -- Enslen, Herve -- Corbille, Anne-Gaelle -- Filhol, Odile -- Nairn, Angus C -- Greengard, Paul -- Herve, Denis -- Girault, Jean-Antoine -- DA10044/DA/NIDA NIH HHS/ -- MH74866/MH/NIMH NIH HHS/ -- P01 DA010044/DA/NIDA NIH HHS/ -- P01 DA010044-020002/DA/NIDA NIH HHS/ -- P01 DA010044-030002/DA/NIDA NIH HHS/ -- P01 DA010044-04/DA/NIDA NIH HHS/ -- P01 DA010044-040002/DA/NIDA NIH HHS/ -- P01 DA010044-05/DA/NIDA NIH HHS/ -- P01 DA010044-050002/DA/NIDA NIH HHS/ -- P01 DA010044-06/DA/NIDA NIH HHS/ -- P01 DA010044-060002/DA/NIDA NIH HHS/ -- P01 DA010044-07/DA/NIDA NIH HHS/ -- P01 DA010044-070002/DA/NIDA NIH HHS/ -- P01 DA010044-08/DA/NIDA NIH HHS/ -- P01 DA010044-080002/DA/NIDA NIH HHS/ -- P01 DA010044-09/DA/NIDA NIH HHS/ -- P01 DA010044-090002/DA/NIDA NIH HHS/ -- P01 DA010044-10/DA/NIDA NIH HHS/ -- P01 DA010044-100002/DA/NIDA NIH HHS/ -- P01 DA010044-11/DA/NIDA NIH HHS/ -- P01 DA010044-110005/DA/NIDA NIH HHS/ -- P01 DA010044-12/DA/NIDA NIH HHS/ -- P01 DA010044-120005/DA/NIDA NIH HHS/ -- P01 DA010044-129002/DA/NIDA NIH HHS/ -- P01 DA010044-13/DA/NIDA NIH HHS/ -- P01 DA010044-130005/DA/NIDA NIH HHS/ -- P01 DA010044-139002/DA/NIDA NIH HHS/ -- P01 DA010044-14/DA/NIDA NIH HHS/ -- P01 DA010044-140005/DA/NIDA NIH HHS/ -- P01 DA010044-149002/DA/NIDA NIH HHS/ -- P01 DA010044-14S1/DA/NIDA NIH HHS/ -- P50 MH074866/MH/NIMH NIH HHS/ -- P50 MH074866-010001/MH/NIMH NIH HHS/ -- P50 MH074866-019001/MH/NIMH NIH HHS/ -- P50 MH074866-020001/MH/NIMH NIH HHS/ -- P50 MH074866-029001/MH/NIMH NIH HHS/ -- P50 MH074866-030001/MH/NIMH NIH HHS/ -- P50 MH074866-039001/MH/NIMH NIH HHS/ -- P50 MH074866-040001/MH/NIMH NIH HHS/ -- P50 MH074866-049001/MH/NIMH NIH HHS/ -- P50 MH074866-050001/MH/NIMH NIH HHS/ -- P50 MH074866-059001/MH/NIMH NIH HHS/ -- England -- Nature. 2008 Jun 12;453(7197):879-84. doi: 10.1038/nature06994. Epub 2008 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Inserm, UMR-S 839, 75005 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18496528" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Dopamine/metabolism ; Dopamine and cAMP-Regulated Phosphoprotein 32/chemistry/genetics/*metabolism ; Food ; Histones/metabolism ; Learning ; Male ; Mice ; Mice, Inbred C57BL ; Motivation ; Motor Activity/physiology ; Neostriatum/cytology ; Neurons/metabolism ; Nucleosomes/*metabolism ; Phosphoprotein Phosphatases/antagonists & inhibitors/*metabolism ; Phosphorylation/drug effects ; Phosphoserine/metabolism ; Protein Transport ; Rats ; *Reward ; *Signal Transduction/drug effects ; Substance-Related Disorders
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    Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration (2008)
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    Publication Date: 2008-05-02
    Description: Phosphoinositide 3-kinases (PI3Ks) signal downstream of multiple cell-surface receptor types. Class IA PI3K isoforms couple to tyrosine kinases and consist of a p110 catalytic subunit (p110alpha, p110beta or p110delta), constitutively bound to one of five distinct p85 regulatory subunits. PI3Ks have been implicated in angiogenesis, but little is known about potential selectivity among the PI3K isoforms and their mechanism of action in endothelial cells during angiogenesis in vivo. Here we show that only p110alpha activity is essential for vascular development. Ubiquitous or endothelial cell-specific inactivation of p110alpha led to embryonic lethality at mid-gestation because of severe defects in angiogenic sprouting and vascular remodelling. p110alpha exerts this critical endothelial cell-autonomous function by regulating endothelial cell migration through the small GTPase RhoA. p110alpha activity is particularly high in endothelial cells and preferentially induced by tyrosine kinase ligands (such as vascular endothelial growth factor (VEGF)-A). In contrast, p110beta in endothelial cells signals downstream of G-protein-coupled receptor (GPCR) ligands such as SDF-1alpha, whereas p110delta is expressed at low level and contributes only minimally to PI3K activity in endothelial cells. These results provide the first in vivo evidence for p110-isoform selectivity in endothelial PI3K signalling during angiogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Graupera, Mariona -- Guillermet-Guibert, Julie -- Foukas, Lazaros C -- Phng, Li-Kun -- Cain, Robert J -- Salpekar, Ashreena -- Pearce, Wayne -- Meek, Stephen -- Millan, Jaime -- Cutillas, Pedro R -- Smith, Andrew J H -- Ridley, Anne J -- Ruhrberg, Christiana -- Gerhardt, Holger -- Vanhaesebroeck, Bart -- BB/C505659/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/C505659/2/Biotechnology and Biological Sciences Research Council/United Kingdom -- G0601093/Medical Research Council/United Kingdom -- G0601093(79633)/Medical Research Council/United Kingdom -- G0700711/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2008 May 29;453(7195):662-6. doi: 10.1038/nature06892. Epub 2008 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Cell Signalling, Institute of Cancer, Queen Mary, University of London, Charterhouse Square, London EC1M 6BQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18449193" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Movement ; Cells, Cultured ; Class I Phosphatidylinositol 3-Kinases ; Endothelial Cells/*cytology/*enzymology ; Female ; Humans ; Mice ; *Neovascularization, Physiologic ; Phosphatidylinositol 3-Kinases/genetics/*metabolism ; RNA Interference ; Rats ; Signal Transduction/drug effects ; Vascular Endothelial Growth Factor A/pharmacology ; Wounds and Injuries ; rho GTP-Binding Proteins/metabolism
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    Molecular biology: power sequencing (2008)
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    Publication Date: 2008-06-27
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4386836/" 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/PMC4386836/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Graveley, Brenton R -- R01 GM062516/GM/NIGMS NIH HHS/ -- R01 GM062516-08/GM/NIGMS NIH HHS/ -- R01 GM067842/GM/NIGMS NIH HHS/ -- R01 GM067842-06/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 Jun 26;453(7199):1197-8. doi: 10.1038/4531197b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18580940" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arabidopsis/genetics ; Expressed Sequence Tags ; *Gene Expression Profiling ; Humans ; Mice ; Oligonucleotide Array Sequence Analysis ; RNA, Messenger/*analysis/*genetics ; Saccharomyces cerevisiae/genetics ; Schizosaccharomyces/genetics ; Transcription, Genetic/genetics
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    Deletion of vascular endothelial growth factor in myeloid cells accelerates tumorigenesis (2008)
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    Publication Date: 2008-11-11
    Description: Angiogenesis and the development of a vascular network are required for tumour progression, and they involve the release of angiogenic factors, including vascular endothelial growth factor (VEGF-A), from both malignant and stromal cell types. Infiltration by cells of the myeloid lineage is a hallmark of many tumours, and in many cases the macrophages in these infiltrates express VEGF-A. Here we show that the deletion of inflammatory-cell-derived VEGF-A attenuates the formation of a typical high-density vessel network, thus blocking the angiogenic switch in solid tumours in mice. Vasculature in tumours lacking myeloid-cell-derived VEGF-A was less tortuous, with increased pericyte coverage and decreased vessel length, indicating vascular normalization. In addition, loss of myeloid-derived VEGF-A decreases the phosphorylation of VEGF receptor 2 (VEGFR2) in tumours, even though overall VEGF-A levels in the tumours are unaffected. However, deletion of myeloid-cell VEGF-A resulted in an accelerated tumour progression in multiple subcutaneous isograft models and an autochthonous transgenic model of mammary tumorigenesis, with less overall tumour cell death and decreased tumour hypoxia. Furthermore, loss of myeloid-cell VEGF-A increased the susceptibility of tumours to chemotherapeutic cytotoxicity. This shows that myeloid-derived VEGF-A is essential for the tumorigenic alteration of vasculature and signalling to VEGFR2, and that these changes act to retard, not promote, tumour progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103772/" 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/PMC3103772/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stockmann, Christian -- Doedens, Andrew -- Weidemann, Alexander -- Zhang, Na -- Takeda, Norihiko -- Greenberg, Joshua I -- Cheresh, David A -- Johnson, Randall S -- AI060840/AI/NIAID NIH HHS/ -- CA118165/CA/NCI NIH HHS/ -- CA82515/CA/NCI NIH HHS/ -- R01 CA082515/CA/NCI NIH HHS/ -- R01 CA082515-12/CA/NCI NIH HHS/ -- R01 CA118165/CA/NCI NIH HHS/ -- England -- Nature. 2008 Dec 11;456(7223):814-8. doi: 10.1038/nature07445. Epub 2008 Nov 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Section, Division of Biological Sciences, Moores Cancer Center, University of California, San Diego, San Diego, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18997773" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anoxia/genetics ; Antineoplastic Agents, Alkylating/pharmacology ; Carcinoma/blood supply/genetics/*metabolism ; Cytotoxins/pharmacology ; Female ; *Gene Deletion ; Gene Expression Regulation, Neoplastic/drug effects ; Male ; Mammary Neoplasms, Experimental/blood supply/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Cells/*metabolism ; Neovascularization, Pathologic/metabolism ; Vascular Endothelial Growth Factor A/*genetics/*metabolism/pharmacology
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    A structural explanation for the binding of endocytic dileucine motifs by the AP2 complex (2009)
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    Publication Date: 2009-01-14
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340503/" 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/PMC4340503/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kelly, Bernard T -- McCoy, Airlie J -- Spate, Kira -- Miller, Sharon E -- Evans, Philip R -- Honing, Stefan -- Owen, David J -- 090909/Wellcome Trust/United Kingdom -- MC_U105178845/Medical Research Council/United Kingdom -- England -- Nature. 2008 Dec 18;456(7224):976-79. doi: 10.1038/nature07422.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19140243" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Protein Complex 2/*chemistry/genetics/*metabolism ; Amino Acid Motifs ; Animals ; Antigens, CD4/*chemistry/*metabolism ; Binding Sites ; Conserved Sequence ; *Endocytosis ; Humans ; Leucine/*metabolism ; Mice ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Subunits/chemistry/genetics/metabolism ; Rats
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    Journal club. A biologist considers a link between jumping genes and immune-system enzymes (2008)
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    Publication Date: 2008-12-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Greally, John -- England -- Nature. 2008 Dec 4;456(7222):549. doi: 10.1038/456549e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Albert Einstein College of Medicine, New York City, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052582" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmune Diseases/enzymology/genetics/*immunology ; Exodeoxyribonucleases/genetics/*metabolism ; Humans ; Immune System/*enzymology/immunology ; Interspersed Repetitive Sequences/*genetics/immunology ; Lupus Erythematosus, Systemic/enzymology/genetics/immunology ; Mice ; Myocarditis/enzymology/genetics/immunology ; Phosphoproteins/genetics/*metabolism ; Retroelements/genetics/immunology
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    Animal research: raise standards to protect patients (2008)
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    Publication Date: 2008-09-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Green, Susan -- England -- Nature. 2008 Sep 25;455(7212):460. doi: 10.1038/455460c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18818630" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Laboratory ; Biomedical Research/*standards ; Humans ; Mice ; *Models, Animal ; Research Design/*standards
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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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    Transcriptional repression mediated by repositioning of genes to the nuclear lamina (2008)
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    Publication Date: 2008-02-15
    Description: Nuclear compartmentalization seems to have an important role in regulating metazoan genes. Although studies on immunoglobulin and other loci have shown a correlation between positioning at the nuclear lamina and gene repression, the functional consequences of this compartmentalization remain untested. We devised an approach for inducible tethering of genes to the inner nuclear membrane (INM), and tested the consequences of such repositioning on gene activity in mouse fibroblasts. Here, using three-dimensional DNA-immunoFISH, we demonstrate repositioning of chromosomal regions to the nuclear lamina that is dependent on breakdown and reformation of the nuclear envelope during mitosis. Moreover, tethering leads to the accumulation of lamin and INM proteins, but not to association with pericentromeric heterochromatin or nuclear pore complexes. Recruitment of genes to the INM can result in their transcriptional repression. Finally, we use targeted adenine methylation (DamID) to show that, as is the case for our model system, inactive immunoglobulin loci at the nuclear periphery are contacted by INM and lamina proteins. We propose that these molecular interactions may be used to compartmentalize and to limit the accessibility of immunoglobulin loci to transcription and recombination factors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reddy, K L -- Zullo, J M -- Bertolino, E -- Singh, H -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 13;452(7184):243-7. doi: 10.1038/nature06727. Epub 2008 Feb 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The University of Chicago, GCIS W522, 929 East 57th Street, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18272965" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Adenine/metabolism ; Animals ; Biological Transport ; *Chromosome Positioning ; DNA-Binding Proteins/metabolism ; Fibroblasts ; *Gene Silencing ; Genes, Reporter/genetics ; Histones/metabolism ; Immunoglobulin Heavy Chains/genetics ; Lamin Type B/metabolism ; Membrane Proteins/metabolism ; Methylation ; Mice ; Mitosis ; Models, Genetic ; Nuclear Lamina/*genetics/*metabolism ; Nuclear Proteins/metabolism ; *Transcription, Genetic
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    Molecular identification of a retinal cell type that responds to upward motion (2008)
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    Publication Date: 2008-03-28
    Description: The retina contains complex circuits of neurons that extract salient information from visual inputs. Signals from photoreceptors are processed by retinal interneurons, integrated by retinal ganglion cells (RGCs) and sent to the brain by RGC axons. Distinct types of RGC respond to different visual features, such as increases or decreases in light intensity (ON and OFF cells, respectively), colour or moving objects. Thus, RGCs comprise a set of parallel pathways from the eye to the brain. The identification of molecular markers for RGC subsets will facilitate attempts to correlate their structure with their function, assess their synaptic inputs and targets, and study their diversification. Here we show, by means of a transgenic marking method, that junctional adhesion molecule B (JAM-B) marks a previously unrecognized class of OFF RGCs in mice. These cells have asymmetric dendritic arbors aligned in a dorsal-to-ventral direction across the retina. Their receptive fields are also asymmetric and respond selectively to stimuli moving in a soma-to-dendrite direction; because the lens reverses the image of the world on the retina, these cells detect upward motion in the visual field. Thus, JAM-B identifies a unique population of RGCs in which structure corresponds remarkably to function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, In-Jung -- Zhang, Yifeng -- Yamagata, Masahito -- Meister, Markus -- Sanes, Joshua R -- England -- Nature. 2008 Mar 27;452(7186):478-82. doi: 10.1038/nature06739.〈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/18368118" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomarkers/analysis ; Cell Adhesion Molecules/*metabolism ; Cell Count ; Cell Shape ; Dendrites/metabolism ; Immunoglobulins ; Mice ; Models, Neurological ; *Motion ; Photic Stimulation ; Retina/*cytology/radiation effects ; Retinal Ganglion Cells/*cytology/*metabolism/radiation effects
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    Animal research: too much faith in models clouds judgement (2008)
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    Publication Date: 2008-09-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suckling, Keith -- England -- Nature. 2008 Sep 25;455(7212):460. doi: 10.1038/455460b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18818629" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomedical Research/*methods/*standards ; Humans ; Mice ; *Models, Animal
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    HIV immunology needs a new direction (2008)
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    Publication Date: 2008-10-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Medzhitov, Ruslan -- Littman, Dan -- England -- Nature. 2008 Oct 2;455(7213):591. doi: 10.1038/455591a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ruslan Medzhitov is professor of immunobiology at Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520, USA. ruslan.medzhitov@yale.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18833256" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/immunology ; Allergy and Immunology/*trends ; Animals ; HIV/*immunology ; HIV Infections/*immunology ; Humans ; Immunity, Innate/*immunology ; Mice ; Species Specificity
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    Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors (2008)
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    Publication Date: 2008-07-03
    Description: Reprogramming of somatic cells is a valuable tool to understand the mechanisms of regaining pluripotency and further opens up the possibility of generating patient-specific pluripotent stem cells. Reprogramming of mouse and human somatic cells into pluripotent stem cells, designated as induced pluripotent stem (iPS) cells, has been possible with the expression of the transcription factor quartet Oct4 (also known as Pou5f1), Sox2, c-Myc and Klf4 (refs 1-11). Considering that ectopic expression of c-Myc causes tumorigenicity in offspring and that retroviruses themselves can cause insertional mutagenesis, the generation of iPS cells with a minimal number of factors may hasten the clinical application of this approach. Here we show that adult mouse neural stem cells express higher endogenous levels of Sox2 and c-Myc than embryonic stem cells, and that exogenous Oct4 together with either Klf4 or c-Myc is sufficient to generate iPS cells from neural stem cells. These two-factor iPS cells are similar to embryonic stem cells at the molecular level, contribute to development of the germ line, and form chimaeras. We propose that, in inducing pluripotency, the number of reprogramming factors can be reduced when using somatic cells that endogenously express appropriate levels of complementing factors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jeong Beom -- Zaehres, Holm -- Wu, Guangming -- Gentile, Luca -- Ko, Kinarm -- Sebastiano, Vittorio -- Arauzo-Bravo, Marcos J -- Ruau, David -- Han, Dong Wook -- Zenke, Martin -- Scholer, Hans R -- England -- Nature. 2008 Jul 31;454(7204):646-50. doi: 10.1038/nature07061. Epub 2008 Jun 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Rontgenstrasse 20, 48149 Munster, NRW, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18594515" target="_blank"〉PubMed〈/a〉
    Keywords: Adult Stem Cells/*cytology/metabolism ; Animals ; Cell Differentiation/genetics ; Cells, Cultured ; *Cellular Reprogramming ; Chimera ; DNA-Binding Proteins/genetics/metabolism ; Female ; Gene Expression Profiling ; Genes, myc/genetics ; HMGB Proteins/genetics/metabolism ; Homeodomain Proteins/genetics ; Kruppel-Like Transcription Factors/genetics/metabolism ; Male ; Mice ; Mice, Nude ; Mice, Transgenic ; Neurons/*cytology ; Octamer Transcription Factor-3/genetics/metabolism ; Pluripotent Stem Cells/*cytology/*metabolism ; Proteins/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; RNA, Untranslated ; SOXB1 Transcription Factors ; Transcription Factors/genetics/metabolism ; Transduction, Genetic
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    Genome-scale DNA methylation maps of pluripotent and differentiated cells (2008)
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    Publication Date: 2008-07-05
    Description: DNA methylation is essential for normal development and has been implicated in many pathologies including cancer. Our knowledge about the genome-wide distribution of DNA methylation, how it changes during cellular differentiation and how it relates to histone methylation and other chromatin modifications in mammals remains limited. Here we report the generation and analysis of genome-scale DNA methylation profiles at nucleotide resolution in mammalian cells. Using high-throughput reduced representation bisulphite sequencing and single-molecule-based sequencing, we generated DNA methylation maps covering most CpG islands, and a representative sampling of conserved non-coding elements, transposons and other genomic features, for mouse embryonic stem cells, embryonic-stem-cell-derived and primary neural cells, and eight other primary tissues. Several key findings emerge from the data. First, DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Second, methylation of CpGs are dynamic epigenetic marks that undergo extensive changes during cellular differentiation, particularly in regulatory regions outside of core promoters. Third, analysis of embryonic-stem-cell-derived and primary cells reveals that 'weak' CpG islands associated with a specific set of developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some primary tumours. More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2896277/" 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/PMC2896277/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meissner, Alexander -- Mikkelsen, Tarjei S -- Gu, Hongcang -- Wernig, Marius -- Hanna, Jacob -- Sivachenko, Andrey -- Zhang, Xiaolan -- Bernstein, Bradley E -- Nusbaum, Chad -- Jaffe, David B -- Gnirke, Andreas -- Jaenisch, Rudolf -- Lander, Eric S -- R01 HG004401/HG/NHGRI NIH HHS/ -- R01 HG004401-02/HG/NHGRI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-04/HG/NHGRI NIH HHS/ -- U54 HG003067-06/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Aug 7;454(7205):766-70. doi: 10.1038/nature07107. Epub 2008 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18600261" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cells, Cultured ; Conserved Sequence ; CpG Islands/genetics ; *DNA Methylation ; Embryonic Stem Cells/cytology/metabolism ; Fibroblasts/cytology ; Genome/genetics ; *Genomics ; Histones/genetics/metabolism ; Male ; Mice ; Neurons/cytology ; Pluripotent Stem Cells/*cytology/*metabolism
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    Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis (2008)
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    Publication Date: 2008-11-07
    Description: Intestinal homeostasis is critical for efficient energy extraction from food and protection from pathogens. Its disruption can lead to an array of severe illnesses with major impacts on public health, such as inflammatory bowel disease characterized by self-destructive intestinal immunity. However, the mechanisms regulating the equilibrium between the large bacterial flora and the immune system remain unclear. Intestinal lymphoid tissues generate flora-reactive IgA-producing B cells, and include Peyer's patches and mesenteric lymph nodes, as well as numerous isolated lymphoid follicles (ILFs). Here we show that peptidoglycan from Gram-negative bacteria is necessary and sufficient to induce the genesis of ILFs in mice through recognition by the NOD1 (nucleotide-binding oligomerization domain containing 1) innate receptor in epithelial cells, and beta-defensin 3- and CCL20-mediated signalling through the chemokine receptor CCR6. Maturation of ILFs into large B-cell clusters requires subsequent detection of bacteria by toll-like receptors. In the absence of ILFs, the composition of the intestinal bacterial community is profoundly altered. Our results demonstrate that intestinal bacterial commensals and the immune system communicate through an innate detection system to generate adaptive lymphoid tissues and maintain intestinal homeostasis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bouskra, Djahida -- Brezillon, Christophe -- Berard, Marion -- Werts, Catherine -- Varona, Rosa -- Boneca, Ivo Gomperts -- Eberl, Gerard -- England -- Nature. 2008 Nov 27;456(7221):507-10. doi: 10.1038/nature07450. Epub 2008 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Pasteur, Laboratory of Lymphoid Tissue Development, CNRS, URA1961.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18987631" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chemokine CCL20/metabolism ; Chimera ; Female ; Germ-Free Life ; Gram-Negative Bacteria/genetics/immunology/isolation & purification/*physiology ; *Homeostasis ; Immunoglobulin A/immunology ; Intestines/immunology/*microbiology/*physiology ; Ligands ; Lymph Nodes/immunology ; Lymphoid Tissue/cytology/*immunology ; Male ; Mice ; Nod1 Signaling Adaptor Protein/deficiency/genetics/immunology/*metabolism ; Peptidoglycan/immunology ; Peyer's Patches/immunology ; Receptors, CCR6/deficiency/genetics/metabolism ; beta-Defensins/metabolism
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    UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes (2008)
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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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    Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B (2008)
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    Publication Date: 2008-07-29
    Description: Epac proteins are activated by binding of the second messenger cAMP and then act as guanine nucleotide exchange factors for Rap proteins. The Epac proteins are involved in the regulation of cell adhesion and insulin secretion. Here we have determined the structure of Epac2 in complex with a cAMP analogue (Sp-cAMPS) and RAP1B by X-ray crystallography and single particle electron microscopy. The structure represents the cAMP activated state of the Epac2 protein with the RAP1B protein trapped in the course of the exchange reaction. Comparison with the inactive conformation reveals that cAMP binding causes conformational changes that allow the cyclic nucleotide binding domain to swing from a position blocking the Rap binding site towards a docking site at the Ras exchange motif domain.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rehmann, Holger -- Arias-Palomo, Ernesto -- Hadders, Michael A -- Schwede, Frank -- Llorca, Oscar -- Bos, Johannes L -- England -- Nature. 2008 Sep 4;455(7209):124-7. doi: 10.1038/nature07187. Epub 2008 Jul 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiological Chemistry, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. h.rehmann@UMCutrecht.nl〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18660803" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Binding Sites ; Carrier Proteins/*chemistry/*metabolism/ultrastructure ; Crystallography, X-Ray ; Cyclic AMP/*analogs & derivatives/chemistry/metabolism ; Enzyme Activation ; Guanine Nucleotide Exchange Factors/*chemistry/*metabolism/ultrastructure ; Humans ; Mice ; Microscopy, Electron ; Models, Molecular ; Protein Binding ; Protein Conformation ; Thionucleotides/*chemistry/*metabolism ; rap GTP-Binding Proteins/chemistry/*metabolism/ultrastructure
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    Trisomy represses Apc(Min)-mediated tumours in mouse models of Down's syndrome (2008)
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    Publication Date: 2008-01-04
    Description: Epidemiological studies spanning more than 50 yr reach conflicting conclusions as to whether there is a lower incidence of solid tumours in people with trisomy 21 (Down's syndrome). We used mouse models of Down's syndrome and of cancer in a biological approach to investigate the relationship between trisomy and the incidence of intestinal tumours. Apc(Min)-mediated tumour number was determined in aneuploid mouse models Ts65Dn, Ts1Rhr and Ms1Rhr. Trisomy for orthologues of about half of the genes on chromosome 21 (Hsa21) in Ts65Dn mice or just 33 of these genes in Ts1Rhr mice resulted in a significant reduction in the number of intestinal tumours. In Ms1Rhr, segmental monosomy for the same 33 genes that are triplicated in Ts1Rhr resulted in an increased number of tumours. Further studies demonstrated that the Ets2 gene contributed most of the dosage-sensitive effect on intestinal tumour number. The action of Ets2 as a repressor when it is overexpressed differs from tumour suppression, which requires normal gene function to prevent cellular transformation. Upregulation of Ets2 and, potentially, other genes involved in this kind of protective effect may provide a prophylactic effect in all individuals, regardless of ploidy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sussan, Thomas E -- Yang, Annan -- Li, Fu -- Ostrowski, Michael C -- Reeves, Roger H -- R01 CA053271/CA/NCI NIH HHS/ -- England -- Nature. 2008 Jan 3;451(7174):73-5. doi: 10.1038/nature06446.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology and The Institute for Genetic Medicine, The 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/18172498" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Chromosomes, Mammalian/genetics ; *Disease Models, Animal ; Down Syndrome/*complications/*genetics/pathology ; Female ; Gene Dosage ; Genes, APC/*physiology ; Intestinal Neoplasms/complications/*genetics/pathology/*prevention & control ; Male ; Mice ; Proto-Oncogene Protein c-ets-2/genetics/metabolism ; Trisomy/*genetics
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    Immunology: cascade into clarity (2008)
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    Publication Date: 2008-01-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sutterwala, Fayyaz S -- Flavell, Richard A -- England -- Nature. 2008 Jan 17;451(7176):254-5. doi: 10.1038/451254a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18202632" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/embryology/genetics/*immunology/microbiology ; Embryonic Development ; Mice ; Nuclear Proteins ; Proteins/genetics/*metabolism ; Signal Transduction
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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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    Functional auditory hair cells produced in the mammalian cochlea by in utero gene transfer (2008)
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    Publication Date: 2008-08-30
    Description: Sensory hair cells in the mammalian cochlea convert mechanical stimuli into electrical impulses that subserve audition. Loss of hair cells and their innervating neurons is the most frequent cause of hearing impairment. Atonal homologue 1 (encoded by Atoh1, also known as Math1) is a basic helix-loop-helix transcription factor required for hair-cell development, and its misexpression in vitro and in vivo generates hair-cell-like cells. Atoh1-based gene therapy to ameliorate auditory and vestibular dysfunction has been proposed. However, the biophysical properties of putative hair cells induced by Atoh1 misexpression have not been characterized. Here we show that in utero gene transfer of Atoh1 produces functional supernumerary hair cells in the mouse cochlea. The induced hair cells display stereociliary bundles, attract neuronal processes and express the ribbon synapse marker carboxy-terminal binding protein 2 (refs 12,13). Moreover, the hair cells are capable of mechanoelectrical transduction and show basolateral conductances with age-appropriate specializations. Our results demonstrate that manipulation of cell fate by transcription factor misexpression produces functional sensory cells in the postnatal mammalian cochlea. We expect that our in utero gene transfer paradigm will enable the design and validation of gene therapies to ameliorate hearing loss in mouse models of human deafness.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925035/" 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/PMC2925035/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gubbels, Samuel P -- Woessner, David W -- Mitchell, John C -- Ricci, Anthony J -- Brigande, John V -- R01 DC008595/DC/NIDCD NIH HHS/ -- R01 DC008595-03/DC/NIDCD NIH HHS/ -- England -- Nature. 2008 Sep 25;455(7212):537-41. doi: 10.1038/nature07265. Epub 2008 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Otolaryngology, Oregon Hearing Research Center, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18754012" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/*genetics/*metabolism ; Cochlea/*cytology/embryology/growth & development/innervation/*metabolism ; Deafness/genetics/therapy ; Disease Models, Animal ; Dyneins/metabolism ; Electric Conductivity ; Female ; Genetic Therapy ; Hair Cells, Auditory/cytology/*physiology ; Humans ; Mechanotransduction, Cellular ; Mice ; Myosins/metabolism ; Pregnancy ; Synapses/metabolism ; *Transfection ; *Uterus
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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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    Mouse miRNA library to open (2008)
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    Publication Date: 2008-07-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dance, Amber -- England -- Nature. 2008 Jul 17;454(7202):264. doi: 10.1038/454264c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18633381" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Specimen Banks ; Gene Expression Regulation ; Mice ; *Mice, Knockout ; *MicroRNAs/genetics/physiology
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    Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia (2008)
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    Publication Date: 2008-06-13
    Description: Osteoclasts are multinucleated haematopoietic cells that resorb bone. Increased osteoclast activity causes osteoporosis, a disorder resulting in a low bone mass and a high risk of fractures. Increased osteoclast size and numbers are also a hallmark of other disorders, such as Paget's disease and multiple myeloma. The protein c-Fos, a component of the AP-1 transcription factor complex, is essential for osteoclast differentiation. Here we show that the Fos-related protein Fra-2 controls osteoclast survival and size. The bones of Fra-2-deficient newborn mice have giant osteoclasts, and signalling through leukaemia inhibitory factor (LIF) and its receptor is impaired. Similarly, newborn animals lacking LIF have giant osteoclasts, and we show that LIF is a direct transcriptional target of Fra-2 and c-Jun. Moreover, bones deficient in Fra-2 and LIF are hypoxic and express increased levels of hypoxia-induced factor 1alpha (HIF1alpha) and Bcl-2. Overexpression of Bcl-2 is sufficient to induce giant osteoclasts in vivo, whereas Fra-2 and LIF affect HIF1alpha through transcriptional modulation of the HIF prolyl hydroxylase PHD2. This pathway is operative in the placenta, because specific inactivation of Fra-2 in the embryo alone does not cause hypoxia or the giant osteoclast phenotype. Thus placenta-induced hypoxia during embryogenesis leads to the formation of giant osteoclasts in young pups. These findings offer potential targets for the treatment of syndromes associated with increased osteoclastogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bozec, Aline -- Bakiri, Latifa -- Hoebertz, Astrid -- Eferl, Robert -- Schilling, Arndt F -- Komnenovic, Vukoslav -- Scheuch, Harald -- Priemel, Matthias -- Stewart, Colin L -- Amling, Michael -- Wagner, Erwin F -- England -- Nature. 2008 Jul 10;454(7201):221-5. doi: 10.1038/nature07019. Epub 2008 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology (I.M.P.), Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18548006" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Anoxia/*metabolism/pathology ; Bone and Bones/cytology/metabolism/pathology ; *Cell Size ; Cell Survival ; DNA-Binding Proteins/metabolism ; Female ; Fos-Related Antigen-2/deficiency/genetics/*metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Hypoxia-Inducible Factor-Proline Dioxygenases ; Immediate-Early Proteins/metabolism ; Leukemia Inhibitory Factor/deficiency/genetics/*metabolism ; Leukemia Inhibitory Factor Receptor alpha Subunit/*metabolism ; Male ; Mice ; Osteoclasts/*cytology/metabolism/pathology ; Procollagen-Proline Dioxygenase ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-bcl-2 ; *Signal Transduction
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    A systematic look at an old problem (2008)
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    Publication Date: 2008-02-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kirkwood, Thomas B L -- BB/C008200/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2008 Feb 7;451(7179):644-7. doi: 10.1038/451644a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Integrated Systems Biology of Ageing and Nutrition, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK. tom.kirkwood@ncl.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18256658" target="_blank"〉PubMed〈/a〉
    Keywords: Age Distribution ; Aging/*physiology ; Animals ; Caenorhabditis elegans/genetics/physiology ; DNA Damage ; Disease Models, Animal ; Geriatrics/trends ; Health ; Humans ; *Life Expectancy/trends ; Longevity/physiology ; Mice ; Models, Biological ; Neoplasms/epidemiology/pathology ; *Systems Biology ; Werner Syndrome/genetics/pathology
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    Melanopsin cells are the principal conduits for rod-cone input to non-image-forming vision (2008)
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    Publication Date: 2008-04-25
    Description: Rod and cone photoreceptors detect light and relay this information through a multisynaptic pathway to the brain by means of retinal ganglion cells (RGCs). These retinal outputs support not only pattern vision but also non-image-forming (NIF) functions, which include circadian photoentrainment and pupillary light reflex (PLR). In mammals, NIF functions are mediated by rods, cones and the melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs). Rod-cone photoreceptors and ipRGCs are complementary in signalling light intensity for NIF functions. The ipRGCs, in addition to being directly photosensitive, also receive synaptic input from rod-cone networks. To determine how the ipRGCs relay rod-cone light information for both image-forming and non-image-forming functions, we genetically ablated ipRGCs in mice. Here we show that animals lacking ipRGCs retain pattern vision but have deficits in both PLR and circadian photoentrainment that are more extensive than those observed in melanopsin knockouts. The defects in PLR and photoentrainment resemble those observed in animals that lack phototransduction in all three photoreceptor classes. These results indicate that light signals for irradiance detection are dissociated from pattern vision at the retinal ganglion cell level, and animals that cannot detect light for NIF functions are still capable of image formation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871301/" 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/PMC2871301/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guler, Ali D -- Ecker, Jennifer L -- Lall, Gurprit S -- Haq, Shafiqul -- Altimus, Cara M -- Liao, Hsi-Wen -- Barnard, Alun R -- Cahill, Hugh -- Badea, Tudor C -- Zhao, Haiqing -- Hankins, Mark W -- Berson, David M -- Lucas, Robert J -- Yau, King-Wai -- Hattar, Samer -- R01 DC006904/DC/NIDCD NIH HHS/ -- R01 DC006904-01/DC/NIDCD NIH HHS/ -- R01 DC006904-02/DC/NIDCD NIH HHS/ -- R01 DC006904-03/DC/NIDCD NIH HHS/ -- R01 DC006904-04/DC/NIDCD NIH HHS/ -- R01 EY006837/EY/NEI NIH HHS/ -- R01 EY006837-16A1/EY/NEI NIH HHS/ -- R01 EY006837-18/EY/NEI NIH HHS/ -- R01 EY006837-20A1/EY/NEI NIH HHS/ -- R01 EY006837-21/EY/NEI NIH HHS/ -- R01 EY014596/EY/NEI NIH HHS/ -- R01 EY014596-01/EY/NEI NIH HHS/ -- R01 EY014596-02/EY/NEI NIH HHS/ -- R01 EY014596-03/EY/NEI NIH HHS/ -- R01 EY014596-04/EY/NEI NIH HHS/ -- R01 EY014596-05/EY/NEI NIH HHS/ -- R01 EY014596-06/EY/NEI NIH HHS/ -- R01 EY017137/EY/NEI NIH HHS/ -- R01 GM076430/GM/NIGMS NIH HHS/ -- R01 GM076430-01/GM/NIGMS NIH HHS/ -- R01 GM076430-02/GM/NIGMS NIH HHS/ -- R01 GM076430-03/GM/NIGMS NIH HHS/ -- R01 GM076430-04/GM/NIGMS NIH HHS/ -- R01 GM076430-05/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 May 1;453(7191):102-5. doi: 10.1038/nature06829. Epub 2008 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18432195" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/cytology/metabolism ; Circadian Rhythm/physiology/radiation effects ; Cues ; Electroretinography ; Light ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Motor Activity/physiology ; Pupil/physiology/radiation effects ; Reflex/physiology/radiation effects ; Retinal Cone Photoreceptor Cells/*metabolism ; Retinal Ganglion Cells/*cytology/*metabolism ; Retinal Rod Photoreceptor Cells/*metabolism ; Rod Opsins/deficiency/genetics/*metabolism ; Vision, Ocular/*physiology/radiation effects ; Visual Acuity/physiology
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    Vancomycin-resistant enterococci exploit antibiotic-induced innate immune deficits (2008)
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    Publication Date: 2008-08-30
    Description: Infection with antibiotic-resistant bacteria, such as vancomycin-resistant Enterococcus (VRE), is a dangerous and costly complication of broad-spectrum antibiotic therapy. How antibiotic-mediated elimination of commensal bacteria promotes infection by antibiotic-resistant bacteria is a fertile area for speculation with few defined mechanisms. Here we demonstrate that antibiotic treatment of mice notably downregulates intestinal expression of RegIIIgamma (also known as Reg3g), a secreted C-type lectin that kills Gram-positive bacteria, including VRE. Downregulation of RegIIIgamma markedly decreases in vivo killing of VRE in the intestine of antibiotic-treated mice. Stimulation of intestinal Toll-like receptor 4 by oral administration of lipopolysaccharide re-induces RegIIIgamma, thereby boosting innate immune resistance of antibiotic-treated mice against VRE. Compromised mucosal innate immune defence, as induced by broad-spectrum antibiotic therapy, can be corrected by selectively stimulating mucosal epithelial Toll-like receptors, providing a potential therapeutic approach to reduce colonization and infection by antibiotic-resistant microbes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663337/" 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/PMC2663337/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brandl, Katharina -- Plitas, George -- Mihu, Coralia N -- Ubeda, Carles -- Jia, Ting -- Fleisher, Martin -- Schnabl, Bernd -- DeMatteo, Ronald P -- Pamer, Eric G -- AI39031/AI/NIAID NIH HHS/ -- AI42135/AI/NIAID NIH HHS/ -- R01 AI039031/AI/NIAID NIH HHS/ -- R01 AI039031-09/AI/NIAID NIH HHS/ -- R01 AI039031-10/AI/NIAID NIH HHS/ -- R01 AI039031-11/AI/NIAID NIH HHS/ -- R01 AI042135/AI/NIAID NIH HHS/ -- R01 AI042135-09/AI/NIAID NIH HHS/ -- R01 AI042135-10/AI/NIAID NIH HHS/ -- R01 AI042135-11/AI/NIAID NIH HHS/ -- R01 AI080619/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Oct 9;455(7214):804-7. doi: 10.1038/nature07250. Epub 2008 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Infectious Diseases Service, Department of Medicine, Immunology Program, Sloan-Kettering Institute, New York, New York, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18724361" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Down-Regulation/drug effects ; Enterococcus/*drug effects/immunology/*physiology ; Immunity, Innate/*drug effects/*immunology ; Intestines/drug effects/immunology/metabolism/microbiology ; Lipopolysaccharides/pharmacology ; Mice ; Myeloid Differentiation Factor 88/deficiency/genetics/metabolism ; Proteins/metabolism ; Signal Transduction ; Toll-Like Receptor 4/immunology/metabolism ; Vancomycin/metabolism/*pharmacology ; *Vancomycin Resistance
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    Imaging of Rab5 activity identifies essential regulators for phagosome maturation (2008)
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    Publication Date: 2008-04-04
    Description: Efficient phagocytosis of apoptotic cells is crucial for tissue homeostasis and the immune response. Rab5 is known as a key regulator of the early endocytic pathway and we have recently shown that Rab5 is also implicated in apoptotic cell engulfment; however, the precise spatio-temporal dynamics of Rab5 activity remain unknown. Here, using a newly developed fluorescence resonance energy transfer biosensor, we describe a change in Rab5 activity during the engulfment of apoptotic thymocytes. Rab5 activity on phagosome membranes began to increase on disassembly of the actin coat encapsulating phagosomes. Rab5 activation was either continuous or repetitive for up to 10 min, but it ended before the collapse of engulfed apoptotic cells. Expression of a dominant-negative mutant of Rab5 delayed this collapse of apoptotic thymocytes, showing a role for Rab5 in phagosome maturation. Disruption of microtubules with nocodazole inhibited Rab5 activation on the phagosome membrane without perturbing the engulfment of apoptotic cells. Furthermore, we found that Gapex-5 is the guanine nucleotide exchange factor essential for Rab5 activation during the engulfment of apoptotic cells. Gapex-5 was bound to a microtubule-tip-associating protein, EB1, whose depletion inhibited Rab5 activation during phagocytosis. We therefore propose a mechanistic model in which the recruitment of Gapex-5 to phagosomes through the microtubule network induces the transient Rab5 activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kitano, Masahiro -- Nakaya, Michio -- Nakamura, Takeshi -- Nagata, Shigekazu -- Matsuda, Michiyuki -- England -- Nature. 2008 May 8;453(7192):241-5. doi: 10.1038/nature06857. Epub 2008 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18385674" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/metabolism ; Animals ; Apoptosis ; Cells, Cultured ; Fluorescence Resonance Energy Transfer ; Genes, Dominant ; Guanine Nucleotide Exchange Factors/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Microtubule-Associated Proteins/metabolism ; Microtubules/drug effects ; Nocodazole/pharmacology ; Phagocytosis/drug effects ; Phagosomes/drug effects/*metabolism ; Swiss 3T3 Cells ; Thymus Gland/cytology/drug effects/metabolism ; rab5 GTP-Binding Proteins/genetics/*metabolism
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    Multi-genetic events collaboratively contribute to Pten-null leukaemia stem-cell formation (2008)
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    Publication Date: 2008-05-09
    Description: Cancer stem cells, which share many common properties and regulatory machineries with normal stem cells, have recently been proposed to be responsible for tumorigenesis and to contribute to cancer resistance. The main challenges in cancer biology are to identify cancer stem cells and to define the molecular events required for transforming normal cells to cancer stem cells. Here we show that Pten deletion in mouse haematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T-lymphoblastic leukaemia (T-ALL). Self-renewable leukaemia stem cells (LSCs) are enriched in the c-Kit(mid)CD3(+)Lin(-) compartment, where unphosphorylated beta-catenin is significantly increased. Conditional ablation of one allele of the beta-catenin gene substantially decreases the incidence and delays the occurrence of T-ALL caused by Pten loss, indicating that activation of the beta-catenin pathway may contribute to the formation or expansion of the LSC population. Moreover, a recurring chromosomal translocation, T(14;15), results in aberrant overexpression of the c-myc oncogene in c-Kit(mid)CD3(+)Lin(-) LSCs and CD3(+) leukaemic blasts, recapitulating a subset of human T-ALL. No alterations in Notch1 signalling are detected in this model, suggesting that Pten inactivation and c-myc overexpression may substitute functionally for Notch1 abnormalities, leading to T-ALL development. Our study indicates that multiple genetic or molecular alterations contribute cooperatively to LSC transformation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840044/" 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/PMC2840044/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Wei -- Lasky, Joseph L -- Chang, Chun-Ju -- Mosessian, Sherly -- Lewis, Xiaoman -- Xiao, Yun -- Yeh, Jennifer E -- Chen, James Y -- Iruela-Arispe, M Luisa -- Varella-Garcia, Marileila -- Wu, Hong -- CA16042/CA/NCI NIH HHS/ -- R01 CA121110/CA/NCI NIH HHS/ -- R01 CA121110-01A1/CA/NCI NIH HHS/ -- England -- Nature. 2008 May 22;453(7194):529-33. doi: 10.1038/nature06933. Epub 2008 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18463637" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD3/metabolism ; Cell Proliferation ; Chromosomes, Mammalian/genetics ; Female ; Hematopoietic Stem Cells/cytology/pathology ; In Situ Hybridization, Fluorescence ; Leukemia-Lymphoma, Adult T-Cell/*pathology ; Male ; Mice ; Neoplastic Stem Cells/*metabolism/*pathology ; PTEN Phosphohydrolase/*deficiency/*genetics ; Proto-Oncogene Proteins c-kit/metabolism ; Proto-Oncogene Proteins c-myc/genetics/metabolism ; Receptors, Antigen, T-Cell/genetics ; Translocation, Genetic ; beta Catenin/metabolism
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    The branching programme of mouse lung development (2008)
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    Publication Date: 2008-05-09
    Description: Mammalian lungs are branched networks containing thousands to millions of airways arrayed in intricate patterns that are crucial for respiration. How such trees are generated during development, and how the developmental patterning information is encoded, have long fascinated biologists and mathematicians. However, models have been limited by a lack of information on the normal sequence and pattern of branching events. Here we present the complete three-dimensional branching pattern and lineage of the mouse bronchial tree, reconstructed from an analysis of hundreds of developmental intermediates. The branching process is remarkably stereotyped and elegant: the tree is generated by three geometrically simple local modes of branching used in three different orders throughout the lung. We propose that each mode of branching is controlled by a genetically encoded subroutine, a series of local patterning and morphogenesis operations, which are themselves controlled by a more global master routine. We show that this hierarchical and modular programme is genetically tractable, and it is ideally suited to encoding and evolving the complex networks of the lung and other branched organs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892995/" 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/PMC2892995/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metzger, Ross J -- Klein, Ophir D -- Martin, Gail R -- Krasnow, Mark A -- R01 CA078711/CA/NCI NIH HHS/ -- R01 CA078711-02/CA/NCI NIH HHS/ -- R01 CA078711-03/CA/NCI NIH HHS/ -- R01 CA078711-04/CA/NCI NIH HHS/ -- R01 CA078711-05/CA/NCI NIH HHS/ -- R01 HL075769/HL/NHLBI NIH HHS/ -- R01 HL075769-01/HL/NHLBI NIH HHS/ -- R01 HL075769-02/HL/NHLBI NIH HHS/ -- R01 HL075769-03/HL/NHLBI NIH HHS/ -- R01 HL075769-04/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Jun 5;453(7196):745-50. doi: 10.1038/nature07005. Epub 2008 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and HHMI, Stanford University School of Medicine, Stanford, California 94305-5307, USA. ross.metzger@ucsf.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18463632" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Animals ; Body Patterning/genetics/*physiology ; Fibroblast Growth Factor 10/metabolism ; Intracellular Signaling Peptides and Proteins ; Lung/*anatomy & histology/cytology/*embryology/metabolism ; Membrane Proteins/metabolism ; Mice ; Models, Biological ; Organogenesis/genetics/*physiology ; Receptor, Fibroblast Growth Factor, Type 2/genetics/metabolism
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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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    Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes (2008)
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    Publication Date: 2008-04-12
    Description: Pseudogenes populate the mammalian genome as remnants of artefactual incorporation of coding messenger RNAs into transposon pathways. Here we show that a subset of pseudogenes generates endogenous small interfering RNAs (endo-siRNAs) in mouse oocytes. These endo-siRNAs are often processed from double-stranded RNAs formed by hybridization of spliced transcripts from protein-coding genes to antisense transcripts from homologous pseudogenes. An inverted repeat pseudogene can also generate abundant small RNAs directly. A second class of endo-siRNAs may enforce repression of mobile genetic elements, acting together with Piwi-interacting RNAs. Loss of Dicer, a protein integral to small RNA production, increases expression of endo-siRNA targets, demonstrating their regulatory activity. Our findings indicate a function for pseudogenes in regulating gene expression by means of the RNA interference pathway and may, in part, explain the evolutionary pressure to conserve argonaute-mediated catalysis in mammals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981145/" 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/PMC2981145/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tam, Oliver H -- Aravin, Alexei A -- Stein, Paula -- Girard, Angelique -- Murchison, Elizabeth P -- Cheloufi, Sihem -- Hodges, Emily -- Anger, Martin -- Sachidanandam, Ravi -- Schultz, Richard M -- Hannon, Gregory J -- P01 CA013106-34/CA/NCI NIH HHS/ -- R01 GM062534/GM/NIGMS NIH HHS/ -- R01 GM062534-07/GM/NIGMS NIH HHS/ -- R01 GM062534-08/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 May 22;453(7194):534-8. doi: 10.1038/nature06904. Epub 2008 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, Watson School of Biological Sciences and Howard Hughes Medical Institute, 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/18404147" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Computational Biology ; DNA Transposable Elements/genetics ; Female ; Gene Expression Regulation, Developmental ; Gene Library ; Mice ; Oocytes/*metabolism ; Pseudogenes/*genetics ; *RNA Interference ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/*genetics ; Ribonuclease III/deficiency/genetics/metabolism
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    Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation (2008)
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    Publication Date: 2008-07-03
    Description: Angiogenesis, the growth of new blood vessels from pre-existing vasculature, is a key process in several pathological conditions, including tumour growth and age-related macular degeneration. Vascular endothelial growth factors (VEGFs) stimulate angiogenesis and lymphangiogenesis by activating VEGF receptor (VEGFR) tyrosine kinases in endothelial cells. VEGFR-3 (also known as FLT-4) is present in all endothelia during development, and in the adult it becomes restricted to the lymphatic endothelium. However, VEGFR-3 is upregulated in the microvasculature of tumours and wounds. Here we demonstrate that VEGFR-3 is highly expressed in angiogenic sprouts, and genetic targeting of VEGFR-3 or blocking of VEGFR-3 signalling with monoclonal antibodies results in decreased sprouting, vascular density, vessel branching and endothelial cell proliferation in mouse angiogenesis models. Stimulation of VEGFR-3 augmented VEGF-induced angiogenesis and sustained angiogenesis even in the presence of VEGFR-2 (also known as KDR or FLK-1) inhibitors, whereas antibodies against VEGFR-3 and VEGFR-2 in combination resulted in additive inhibition of angiogenesis and tumour growth. Furthermore, genetic or pharmacological disruption of the Notch signalling pathway led to widespread endothelial VEGFR-3 expression and excessive sprouting, which was inhibited by blocking VEGFR-3 signals. Our results implicate VEGFR-3 as a regulator of vascular network formation. Targeting VEGFR-3 may provide additional efficacy for anti-angiogenic therapies, especially towards vessels that are resistant to VEGF or VEGFR-2 inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tammela, Tuomas -- Zarkada, Georgia -- Wallgard, Elisabet -- Murtomaki, Aino -- Suchting, Steven -- Wirzenius, Maria -- Waltari, Marika -- Hellstrom, Mats -- Schomber, Tibor -- Peltonen, Reetta -- Freitas, Catarina -- Duarte, Antonio -- Isoniemi, Helena -- Laakkonen, Pirjo -- Christofori, Gerhard -- Yla-Herttuala, Seppo -- Shibuya, Masabumi -- Pytowski, Bronislaw -- Eichmann, Anne -- Betsholtz, Christer -- Alitalo, Kari -- 5 R01 HL075183-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2008 Jul 31;454(7204):656-60. doi: 10.1038/nature07083. Epub 2008 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki and the Haartman Institute University of Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18594512" target="_blank"〉PubMed〈/a〉
    Keywords: Angiogenesis Inhibitors/pharmacology ; Animals ; Antibodies, Monoclonal/pharmacology ; Cell Line, Tumor ; Dipeptides/pharmacology ; Down-Regulation ; Endothelial Cells/metabolism ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Ligands ; Mice ; Mice, Inbred BALB C ; Mice, Transgenic ; Neoplasms/*blood supply/drug therapy ; Neovascularization, Pathologic/genetics/*metabolism ; Receptors, Notch/metabolism ; Signal Transduction ; Vascular Endothelial Growth Factor Receptor-3/*antagonists & ; inhibitors/*metabolism
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    Mitofusin 2 tethers endoplasmic reticulum to mitochondria (2008)
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    Publication Date: 2008-12-05
    Description: Juxtaposition between endoplasmic reticulum (ER) and mitochondria is a common structural feature, providing the physical basis for intercommunication during Ca(2+) signalling; yet, the molecular mechanisms controlling this interaction are unknown. Here we show that mitofusin 2, a mitochondrial dynamin-related protein mutated in the inherited motor neuropathy Charcot-Marie-Tooth type IIa, is enriched at the ER-mitochondria interface. Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology and loosens ER-mitochondria interactions, thereby reducing the efficiency of mitochondrial Ca(2+) uptake in response to stimuli that generate inositol-1,4,5-trisphosphate. An in vitro assay as well as genetic and biochemical evidences support a model in which mitofusin 2 on the ER bridges the two organelles by engaging in homotypic and heterotypic complexes with mitofusin 1 or 2 on the surface of mitochondria. Thus, mitofusin 2 tethers ER to mitochondria, a juxtaposition required for efficient mitochondrial Ca(2+) uptake.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Brito, Olga Martins -- Scorrano, Luca -- TCR07002/Telethon/Italy -- England -- Nature. 2008 Dec 4;456(7222):605-10. doi: 10.1038/nature07534.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dulbecco-Telethon Institute, Venetian Institute of Molecular Medicine, Via Orus 2, 35129 Padova, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19052620" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/metabolism ; Calcium Signaling ; Charcot-Marie-Tooth Disease/genetics ; Endoplasmic Reticulum/*metabolism ; Fibroblasts ; GTP Phosphohydrolases/deficiency/genetics/*metabolism ; HeLa Cells ; Humans ; Inositol 1,4,5-Trisphosphate/metabolism ; Membrane Proteins/deficiency/genetics/*metabolism ; Mice ; Mitochondria/*metabolism ; Mitochondrial Proteins/deficiency/genetics/*metabolism ; Organelle Shape
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    NF-kappaB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1alpha (2008)
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    Publication Date: 2008-04-25
    Description: The hypoxic response is an ancient stress response triggered by low ambient oxygen (O2) (ref. 1) and controlled by hypoxia-inducible transcription factor-1 (HIF-1), whose alpha subunit is rapidly degraded under normoxia but stabilized when O2-dependent prolyl hydroxylases (PHDs) that target its O2-dependent degradation domain are inhibited. Thus, the amount of HIF-1alpha, which controls genes involved in energy metabolism and angiogenesis, is regulated post-translationally. Another ancient stress response is the innate immune response, regulated by several transcription factors, among which NF-kappaB plays a central role. NF-kappaB activation is controlled by IkappaB kinases (IKK), mainly IKK-beta, needed for phosphorylation-induced degradation of IkappaB inhibitors in response to infection and inflammation. IKK-beta is modestly activated in hypoxic cell cultures when PHDs that attenuate its activation are inhibited. However, defining the relationship between NF-kappaB and HIF-1alpha has proven elusive. Using in vitro systems, it was reported that HIF-1alpha activates NF-kappaB, that NF-kappaB controls HIF-1alpha transcription and that HIF-1alpha activation may be concurrent with inhibition of NF-kappaB. Here we show, with the use of mice lacking IKK-beta in different cell types, that NF-kappaB is a critical transcriptional activator of HIF-1alpha and that basal NF-kappaB activity is required for HIF-1alpha protein accumulation under hypoxia in cultured cells and in the liver and brain of hypoxic animals. IKK-beta deficiency results in defective induction of HIF-1alpha target genes including vascular endothelial growth factor. IKK-beta is also essential for HIF-1alpha accumulation in macrophages experiencing a bacterial infection. Hence, IKK-beta is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669289/" 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/PMC2669289/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rius, Jordi -- Guma, Monica -- Schachtrup, Christian -- Akassoglou, Katerina -- Zinkernagel, Annelies S -- Nizet, Victor -- Johnson, Randall S -- Haddad, Gabriel G -- Karin, Michael -- P41 RR004050/RR/NCRR NIH HHS/ -- P41 RR004050-208577/RR/NCRR NIH HHS/ -- R01 AI043477/AI/NIAID NIH HHS/ -- R01 AI043477-12/AI/NIAID NIH HHS/ -- R01 CA118165/CA/NCI NIH HHS/ -- England -- Nature. 2008 Jun 5;453(7196):807-11. doi: 10.1038/nature06905. Epub 2008 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Signal Transduction, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18432192" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anoxia/*genetics/immunology/*metabolism ; Brain/metabolism ; Cell Hypoxia/genetics/physiology ; *Gene Expression Regulation ; Hypoxia-Inducible Factor 1, alpha Subunit/*genetics/metabolism ; I-kappa B Kinase/genetics/metabolism ; Immunity, Innate/genetics/*physiology ; Inflammation ; Liver/metabolism ; Macrophages/metabolism/microbiology ; Mice ; NF-kappa B/*metabolism ; *Transcription, Genetic
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    Rapid appearance and local toxicity of amyloid-beta plaques in a mouse model of Alzheimer's disease (2008)
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    Publication Date: 2008-02-08
    Description: Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer's disease. A fundamental tenet of the amyloid hypothesis of Alzheimer's disease is that the deposition of amyloid-beta precedes and induces the neuronal abnormalities that underlie dementia. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1-2 days of a new plaque's appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3264491/" 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/PMC3264491/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meyer-Luehmann, Melanie -- Spires-Jones, Tara L -- Prada, Claudia -- Garcia-Alloza, Monica -- de Calignon, Alix -- Rozkalne, Anete -- Koenigsknecht-Talboo, Jessica -- Holtzman, David M -- Bacskai, Brian J -- Hyman, Bradley T -- P30 DK056341/DK/NIDDK NIH HHS/ -- P30 DK056341-07/DK/NIDDK NIH HHS/ -- P30 DK056341-08/DK/NIDDK NIH HHS/ -- R01 AG008487/AG/NIA NIH HHS/ -- R01 AG008487-20/AG/NIA NIH HHS/ -- England -- Nature. 2008 Feb 7;451(7179):720-4. doi: 10.1038/nature06616.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Alzheimer's Disease Research Laboratory, Department of Neurology, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18256671" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/genetics/metabolism/*pathology ; Amyloid beta-Peptides/genetics/metabolism/*toxicity ; Animals ; Axons/metabolism ; *Disease Models, Animal ; Disease Progression ; Mice ; Mice, Transgenic ; Microglia/metabolism ; Neurites/metabolism/pathology ; Plaque, Amyloid/genetics/metabolism/*pathology ; Time Factors
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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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    Phosphoinositide signalling links O-GlcNAc transferase to insulin resistance (2008)
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    Publication Date: 2008-02-22
    Description: Glucose flux through the hexosamine biosynthetic pathway leads to the post-translational modification of cytoplasmic and nuclear proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc). This tandem system serves as a nutrient sensor to couple systemic metabolic status to cellular regulation of signal transduction, transcription, and protein degradation. Here we show that O-GlcNAc transferase (OGT) harbours a previously unrecognized type of phosphoinositide-binding domain. After induction with insulin, phosphatidylinositol 3,4,5-trisphosphate recruits OGT from the nucleus to the plasma membrane, where the enzyme catalyses dynamic modification of the insulin signalling pathway by O-GlcNAc. This results in the alteration in phosphorylation of key signalling molecules and the attenuation of insulin signal transduction. Hepatic overexpression of OGT impairs the expression of insulin-responsive genes and causes insulin resistance and dyslipidaemia. These findings identify a molecular mechanism by which nutritional cues regulate insulin signalling through O-GlcNAc, and underscore the contribution of this modification to the aetiology of insulin resistance and type 2 diabetes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Xiaoyong -- Ongusaha, Pat P -- Miles, Philip D -- Havstad, Joyce C -- Zhang, Fengxue -- So, W Venus -- Kudlow, Jeffrey E -- Michell, Robert H -- Olefsky, Jerrold M -- Field, Seth J -- Evans, Ronald M -- P30 CA014195/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Feb 21;451(7181):964-9. doi: 10.1038/nature06668.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18288188" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylglucosamine/metabolism/pharmacology ; Animals ; COS Cells ; Cell Membrane/metabolism ; Cercopithecus aethiops ; Insulin/pharmacology ; Insulin Resistance/*physiology ; Lipid Metabolism ; Liver/enzymology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; N-Acetylglucosaminyltransferases/chemistry/genetics/*metabolism ; Phosphatidylinositol Phosphates/metabolism ; Phosphatidylinositols/*metabolism ; Phosphorylation/drug effects ; Protein Structure, Tertiary ; Protein Transport ; *Second Messenger Systems/drug effects
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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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    TMEM16A confers receptor-activated calcium-dependent chloride conductance (2008)
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    Publication Date: 2008-08-30
    Description: Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+) and Ca(2+)-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca(2+)-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca(2+)-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca(2+)-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Young Duk -- Cho, Hawon -- Koo, Jae Yeon -- Tak, Min Ho -- Cho, Yeongyo -- Shim, Won-Sik -- Park, Seung Pyo -- Lee, Jesun -- Lee, Byeongjun -- Kim, Byung-Moon -- Raouf, Ramin -- Shin, Young Ki -- Oh, Uhtaek -- Wellcome Trust/United Kingdom -- England -- Nature. 2008 Oct 30;455(7217):1210-5. doi: 10.1038/nature07313. Epub 2008 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sensory Research Center, CRI, College of Pharmacy, Seoul National University, Seoul 151-742, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18724360" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/*metabolism/pharmacology ; Chloride Channels/chemistry/deficiency/genetics/*metabolism ; Chlorides/*metabolism ; Electric Conductivity ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Intracellular Space/drug effects/metabolism ; Ion Transport/drug effects ; Mice ; Oocytes/metabolism ; Pilocarpine/pharmacology ; RNA, Small Interfering/genetics/metabolism ; Rats ; Receptors, G-Protein-Coupled/*metabolism ; Salivation/drug effects ; Xenopus
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    Genome-wide screen reveals APC-associated RNAs enriched in cell protrusions (2008)
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    Publication Date: 2008-05-03
    Description: RNA localization is important for the establishment and maintenance of polarity in multiple cell types. Localized RNAs are usually transported along microtubules or actin filaments and become anchored at their destination to some underlying subcellular structure. Retention commonly involves actin or actin-associated proteins, although cytokeratin filaments and dynein anchor certain RNAs. RNA localization is important for diverse processes ranging from cell fate determination to synaptic plasticity; however, so far there have been few comprehensive studies of localized RNAs in mammalian cells. Here we have addressed this issue, focusing on migrating fibroblasts that polarize to form a leading edge and a tail in a process that involves asymmetric distribution of RNAs. We used a fractionation scheme combined with microarrays to identify, on a genome-wide scale, RNAs that localize in protruding pseudopodia of mouse fibroblasts in response to migratory stimuli. We find that a diverse group of RNAs accumulates in such pseudopodial protrusions. Through their 3' untranslated regions these transcripts are anchored in granules concentrated at the plus ends of detyrosinated microtubules. RNAs in the granules associate with the adenomatous polyposis coli (APC) tumour suppressor and the fragile X mental retardation protein (FMRP). APC is required for the accumulation of transcripts in protrusions. Our results suggest a new type of RNA anchoring mechanism as well as a new, unanticipated function for APC in localizing RNAs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782773/" 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/PMC2782773/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mili, Stavroula -- Moissoglu, Konstadinos -- Macara, Ian G -- R01 GM070902/GM/NIGMS NIH HHS/ -- R01 GM070902-05/GM/NIGMS NIH HHS/ -- England -- Nature. 2008 May 1;453(7191):115-9. doi: 10.1038/nature06888.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology, Center for Cell Signaling, University of Virginia, HSC, Charlottesville, Virginia 22908-0577, USA. sm2ju@virginia.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18451862" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/genetics/metabolism ; Adenomatous Polyposis Coli Protein/*metabolism ; Animals ; Cell Movement ; Cell Polarity ; Fibroblasts/cytology ; Fragile X Mental Retardation Protein/metabolism ; Genome/genetics ; *Genomics ; Humans ; Mice ; Microtubules/chemistry/metabolism ; NIH 3T3 Cells ; Oligonucleotide Array Sequence Analysis ; Pseudopodia/*genetics/*metabolism ; RNA/analysis/genetics/isolation & purification/*metabolism ; *RNA Transport
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    Reversal of pathological pain through specific spinal GABAA receptor subtypes (2008)
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    Publication Date: 2008-01-19
    Description: Inflammatory diseases and neuropathic insults are frequently accompanied by severe and debilitating pain, which can become chronic and often unresponsive to conventional analgesic treatment. A loss of synaptic inhibition in the spinal dorsal horn is considered to contribute significantly to this pain pathology. Facilitation of spinal gamma-aminobutyric acid (GABA)ergic neurotransmission through modulation of GABA(A) receptors should be able to compensate for this loss. With the use of GABA(A)-receptor point-mutated knock-in mice in which specific GABA(A) receptor subtypes have been selectively rendered insensitive to benzodiazepine-site ligands, we show here that pronounced analgesia can be achieved by specifically targeting spinal GABA(A) receptors containing the alpha2 and/or alpha3 subunits. We show that their selective activation by the non-sedative ('alpha1-sparing') benzodiazepine-site ligand L-838,417 (ref. 13) is highly effective against inflammatory and neuropathic pain yet devoid of unwanted sedation, motor impairment and tolerance development. L-838,417 not only diminished the nociceptive input to the brain but also reduced the activity of brain areas related to the associative-emotional components of pain, as shown by functional magnetic resonance imaging in rats. These results provide a rational basis for the development of subtype-selective GABAergic drugs for the treatment of chronic pain, which is often refractory to classical analgesics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Knabl, Julia -- Witschi, Robert -- Hosl, Katharina -- Reinold, Heiko -- Zeilhofer, Ulrike B -- Ahmadi, Seifollah -- Brockhaus, Johannes -- Sergejeva, Marina -- Hess, Andreas -- Brune, Kay -- Fritschy, Jean-Marc -- Rudolph, Uwe -- Mohler, Hanns -- Zeilhofer, Hanns Ulrich -- England -- Nature. 2008 Jan 17;451(7176):330-4. doi: 10.1038/nature06493.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nurnberg, D-91054 Erlangen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18202657" target="_blank"〉PubMed〈/a〉
    Keywords: Analgesics/administration & dosage/metabolism/pharmacology/therapeutic use ; Animals ; Brain/drug effects/physiology ; Capsaicin/pharmacology ; Chronic Disease/drug therapy ; Diazepam/administration & dosage/metabolism/pharmacology ; Disease Models, Animal ; Fluorobenzenes/metabolism/pharmacology ; Formaldehyde ; Ganglia, Spinal/cytology/metabolism ; Hot Temperature ; Inflammation/chemically induced/drug therapy ; Male ; Mice ; Neurons/drug effects/metabolism ; Organ Specificity ; Pain/chemically induced/*drug therapy/*metabolism/prevention & control ; Protein Isoforms/chemistry/metabolism ; Protein Subunits/chemistry/metabolism ; Rats ; Rats, Wistar ; Receptors, GABA-A/chemistry/genetics/*metabolism ; Spinal Cord/cytology/drug effects/*metabolism/physiopathology ; Triazoles/metabolism/pharmacology
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    Physiology: Courier service for ammonia (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-11-21
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674619/" 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/PMC2674619/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Knepper, Mark A -- Z01 HL001285-21/Intramural NIH HHS/ -- Z99 HL999999/Intramural NIH HHS/ -- England -- Nature. 2008 Nov 20;456(7220):336-7. doi: 10.1038/456336a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19020610" target="_blank"〉PubMed〈/a〉
    Keywords: Acidosis/physiopathology ; Animals ; Cation Transport Proteins/deficiency/genetics/*metabolism ; Epididymis/cytology/metabolism ; Fertility/*physiology ; Humans ; Hydrogen-Ion Concentration ; Kidney/*physiology ; Male ; Membrane Glycoproteins/deficiency/genetics/*metabolism ; Mice ; Quaternary Ammonium Compounds/*urine
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    Chromatin dynamics during epigenetic reprogramming in the mouse germ line (2008)
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    Publication Date: 2008-03-21
    Description: A unique feature of the germ cell lineage is the generation of totipotency. A critical event in this context is DNA demethylation and the erasure of parental imprints in mouse primordial germ cells (PGCs) on embryonic day 11.5 (E11.5) after they enter into the developing gonads. Little is yet known about the mechanism involved, except that it is apparently an active process. We have examined the associated changes in the chromatin to gain further insights into this reprogramming event. Here we show that the chromatin changes occur in two steps. The first changes in nascent PGCs at E8.5 establish a distinctive chromatin signature that is reminiscent of pluripotency. Next, when PGCs are residing in the gonads, major changes occur in nuclear architecture accompanied by an extensive erasure of several histone modifications and exchange of histone variants. Furthermore, the histone chaperones HIRA and NAP-1 (NAP111), which are implicated in histone exchange, accumulate in PGC nuclei undergoing reprogramming. We therefore suggest that the mechanism of histone replacement is critical for these chromatin rearrangements to occur. The marked chromatin changes are intimately linked with genome-wide DNA demethylation. On the basis of the timing of the observed events, we propose that if DNA demethylation entails a DNA repair-based mechanism, the evident histone replacement would represent a repair-induced response event rather than being a prerequisite.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847605/" 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/PMC3847605/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hajkova, Petra -- Ancelin, Katia -- Waldmann, Tanja -- Lacoste, Nicolas -- Lange, Ulrike C -- Cesari, Francesca -- Lee, Caroline -- Almouzni, Genevieve -- Schneider, Robert -- Surani, M Azim -- 083089/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2008 Apr 17;452(7189):877-81. doi: 10.1038/nature06714. Epub 2008 Mar 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, 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/18354397" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromatin/*metabolism ; *Chromatin Assembly and Disassembly ; DNA Methylation ; *Epigenesis, Genetic ; Germ Cells/*metabolism ; Gonads/cytology/metabolism ; Histones/metabolism ; Mice ; Stem Cells/metabolism
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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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    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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    Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart (2008)
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    Publication Date: 2008-02-01
    Description: Understanding cellular response to environmental stress has broad implications for human disease. AMP-activated protein kinase (AMPK) orchestrates the regulation of energy-generating and -consuming pathways, and protects the heart against ischaemic injury and apoptosis. A role for circulating hormones such as adiponectin and leptin in the activation of AMPK has received recent attention. Whether local autocrine and paracrine factors within target organs such as the heart modulate AMPK is unknown. Here we show that macrophage migration inhibitory factor (MIF), an upstream regulator of inflammation, is released in the ischaemic heart, where it stimulates AMPK activation through CD74, promotes glucose uptake and protects the heart during ischaemia-reperfusion injury. Germline deletion of the Mif gene impairs ischaemic AMPK signalling in the mouse heart. Human fibroblasts with a low-activity MIF promoter polymorphism have diminished MIF release and AMPK activation during hypoxia. Thus, MIF modulates the activation of the cardioprotective AMPK pathway during ischaemia, functionally linking inflammation and metabolism in the heart. We anticipate that genetic variation in MIF expression may impact on the response of the human heart to ischaemia by the AMPK pathway, and that diagnostic MIF genotyping might predict risk in patients with coronary artery disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miller, Edward J -- Li, Ji -- Leng, Lin -- McDonald, Courtney -- Atsumi, Toshiya -- Bucala, Richard -- Young, Lawrence H -- England -- Nature. 2008 Jan 31;451(7178):578-82. doi: 10.1038/nature06504.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Medicine Section of the Department of Internal Medicine, 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/18235500" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases ; Animals ; Anoxia/enzymology/genetics/metabolism ; Antigens, Differentiation, B-Lymphocyte/genetics/metabolism ; Coronary Artery Disease/genetics ; Enzyme Activation ; Genetic Predisposition to Disease ; Genotype ; Glucose/metabolism ; Histocompatibility Antigens Class II/genetics/metabolism ; Humans ; Macrophage Migration-Inhibitory Factors/deficiency/genetics/*metabolism/secretion ; Mice ; Multienzyme Complexes/*metabolism ; Myocardial Ischemia/enzymology/genetics/*metabolism ; Myocardial Reperfusion Injury/physiopathology/prevention & control ; Myocardium/enzymology/metabolism ; Polymorphism, Genetic/genetics ; Promoter Regions, Genetic/genetics ; Protein-Serine-Threonine Kinases/*metabolism ; Rats ; Signal Transduction
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    Sarcolemma-localized nNOS is required to maintain activity after mild exercise (2008)
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    Publication Date: 2008-10-28
    Description: Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients, and some patients experience severe fatigue without any demonstrable somatic disease. Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown. With no treatment available, this form of inactivity is a major determinant of disability. Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase (nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS-null mice do not have muscle pathology and have no loss of muscle-specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was only relieved by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signalling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction-induced signalling from sarcolemma-localized nNOS, which decreases cGMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise-induced signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588643/" 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/PMC2588643/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kobayashi, Yvonne M -- Rader, Erik P -- Crawford, Robert W -- Iyengar, Nikhil K -- Thedens, Daniel R -- Faulkner, John A -- Parikh, Swapnesh V -- Weiss, Robert M -- Chamberlain, Jeffrey S -- Moore, Steven A -- Campbell, Kevin P -- F32 AR048742-01/AR/NIAMS NIH HHS/ -- F32 AR048742-02/AR/NIAMS NIH HHS/ -- K26 RR017369/RR/NCRR NIH HHS/ -- K26 RR017369-01A1/RR/NCRR NIH HHS/ -- K26 RR017369-02/RR/NCRR NIH HHS/ -- K26 RR017369-03/RR/NCRR NIH HHS/ -- K26 RR017369-04/RR/NCRR NIH HHS/ -- K26 RR017369-05/RR/NCRR NIH HHS/ -- R01 AG033610/AG/NIA NIH HHS/ -- R01 AR051199/AR/NIAMS NIH HHS/ -- R01 AR051199-01/AR/NIAMS NIH HHS/ -- T32 HL007121/HL/NHLBI NIH HHS/ -- T32 HL007121-26/HL/NHLBI NIH HHS/ -- T32 HL007121-27/HL/NHLBI NIH HHS/ -- U54 NS053672/NS/NINDS NIH HHS/ -- U54 NS053672-01/NS/NINDS NIH HHS/ -- U54 NS053672-02/NS/NINDS NIH HHS/ -- U54 NS053672-02S1/NS/NINDS NIH HHS/ -- U54 NS053672-03/NS/NINDS NIH HHS/ -- U54 NS053672-04/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Nov 27;456(7221):511-5. doi: 10.1038/nature07414. Epub 2008 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of Iowa, Roy J. and Lucille A. Carver College of Medicine, 4283 Carver Biomedical Research Building, 285 Newton Road, Iowa City, Iowa 52242-1101, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18953332" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cyclic GMP/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 5 ; *Disease Models, Animal ; Edema/drug therapy/etiology/prevention & control ; Enzyme Activation ; Exercise/*physiology ; Fatigue/pathology/*physiopathology ; Hemodynamics/drug effects ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Muscle, Skeletal/blood supply/cytology/enzymology/physiopathology ; Muscular Diseases/enzymology/pathology ; Nitric Oxide/metabolism ; Nitric Oxide Synthase Type I/deficiency/genetics/*metabolism ; Phosphodiesterase 5 Inhibitors ; Protein Transport ; Sarcolemma/*enzymology ; Signal Transduction
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    A skin microRNA promotes differentiation by repressing 'stemness' (2008)
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    Publication Date: 2008-03-04
    Description: In stratified epithelial tissues, homeostasis relies on the self-renewing capacity of stem cells located within the innermost basal layer. As basal cells become suprabasal, they lose proliferative potential and embark on a terminal differentiation programme. Here, we show that microRNA-203 is induced in the skin concomitantly with stratification and differentiation. By altering miR-203's spatiotemporal expression in vivo, we show that miR-203 promotes epidermal differentiation by restricting proliferative potential and inducing cell-cycle exit. We identify p63 as one of the conserved targets of miR-203 across vertebrates. Notably, p63 is an essential regulator of stem-cell maintenance in stratified epithelial tissues. We show that miR-203 directly represses the expression of p63: it fails to switch off suprabasally when either Dicer1 or miR-203 is absent and it becomes repressed basally when miR-203 is prematurely expressed. Our findings suggest that miR-203 defines a molecular boundary between proliferative basal progenitors and terminally differentiating suprabasal cells, ensuring proper identity of neighbouring layers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346711/" 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/PMC4346711/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yi, Rui -- Poy, Matthew N -- Stoffel, Markus -- Fuchs, Elaine -- R01 AR050452/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 13;452(7184):225-9. doi: 10.1038/nature06642. Epub 2008 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The Rockefeller University, New York City, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18311128" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/genetics ; Animals ; Base Sequence ; Cell Cycle ; *Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Computational Biology ; Epidermis/cytology/metabolism ; Gene Expression Regulation ; Humans ; Keratinocytes/cytology/metabolism ; Mice ; Mice, Knockout ; MicroRNAs/antagonists & inhibitors/genetics/*metabolism ; Skin/*cytology/*metabolism ; Stem Cells/*cytology ; Zebrafish/genetics
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    The ground state of embryonic stem cell self-renewal (2008)
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    Publication Date: 2008-05-24
    Description: In the three decades since pluripotent mouse embryonic stem (ES) cells were first described they have been derived and maintained by using various empirical combinations of feeder cells, conditioned media, cytokines, growth factors, hormones, fetal calf serum, and serum extracts. Consequently ES-cell self-renewal is generally considered to be dependent on multifactorial stimulation of dedicated transcriptional circuitries, pre-eminent among which is the activation of STAT3 by cytokines (ref. 8). Here we show, however, that extrinsic stimuli are dispensable for the derivation, propagation and pluripotency of ES cells. Self-renewal is enabled by the elimination of differentiation-inducing signalling from mitogen-activated protein kinase. Additional inhibition of glycogen synthase kinase 3 consolidates biosynthetic capacity and suppresses residual differentiation. Complete bypass of cytokine signalling is confirmed by isolating ES cells genetically devoid of STAT3. These findings reveal that ES cells have an innate programme for self-replication that does not require extrinsic instruction. This property may account for their latent tumorigenicity. The delineation of minimal requirements for self-renewal now provides a defined platform for the precise description and dissection of the pluripotent state.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ying, Qi-Long -- Wray, Jason -- Nichols, Jennifer -- Batlle-Morera, Laura -- Doble, Bradley -- Woodgett, James -- Cohen, Philip -- Smith, Austin -- 12043/Canadian Institutes of Health Research/Canada -- 12858/Canadian Institutes of Health Research/Canada -- G15381/2/Biotechnology and Biological Sciences Research Council/United Kingdom -- G9806702/Medical Research Council/United Kingdom -- MC_U127084348/Medical Research Council/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2008 May 22;453(7194):519-23. doi: 10.1038/nature06968.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Stem Cell and Regenerative Medicine, Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, 1501 San Pablo Street, ZNI 529, Los Angeles, California 90033, USA. qying@keck.usc.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18497825" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzamides/pharmacology ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cells, Cultured ; Diphenylamine/analogs & derivatives/pharmacology ; Embryonic Stem Cells/*cytology/drug effects/metabolism ; Glycogen Synthase Kinase 3/antagonists & inhibitors/metabolism ; MAP Kinase Signaling System/drug effects ; Mice ; Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism ; Pluripotent Stem Cells/cytology/drug effects/metabolism ; Pyridines/pharmacology ; Pyrimidines/pharmacology ; Regeneration/drug effects/*physiology ; STAT3 Transcription Factor/deficiency/genetics/metabolism
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    Vascular normalization in Rgs5-deficient tumours promotes immune destruction (2008)
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    Publication Date: 2008-04-18
    Description: The vasculature of solid tumours is morphologically aberrant and characterized by dilated and fragile vessels, intensive vessel sprouting and loss of hierarchical architecture. Constant vessel remodelling leads to spontaneous haemorrhages and increased interstitial fluid pressure in the tumour environment. Tumour-related angiogenesis supports tumour growth and is also a major obstacle for successful immune therapy as it prevents migration of immune effector cells into established tumour parenchyma. The molecular mechanisms for these angiogenic alterations are largely unknown. Here we identify regulator of G-protein signalling 5 (Rgs5) as a master gene responsible for the abnormal tumour vascular morphology in mice. Loss of Rgs5 results in pericyte maturation, vascular normalization and consequent marked reductions in tumour hypoxia and vessel leakiness. These vascular and intratumoral changes enhance influx of immune effector cells into tumour parenchyma and markedly prolong survival of tumour-bearing mice. This is the first demonstration, to our knowledge, of reduced tumour angiogenesis and improved immune therapeutic outcome on loss of a vascular gene function and establishes a previously unrecognized role of G-protein signalling in tumour angiogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hamzah, Juliana -- Jugold, Manfred -- Kiessling, Fabian -- Rigby, Paul -- Manzur, Mitali -- Marti, Hugo H -- Rabie, Tamer -- Kaden, Sylvia -- Grone, Hermann-Josef -- Hammerling, Gunter J -- Arnold, Bernd -- Ganss, Ruth -- England -- Nature. 2008 May 15;453(7193):410-4. doi: 10.1038/nature06868. Epub 2008 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Western Australian Institute for Medical Research, UWA Centre for Medical Research, Perth, Western Australia 6000, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18418378" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Capillary Permeability ; Cell Hypoxia/physiology ; Female ; Male ; Mice ; Neovascularization, Pathologic/*prevention & control ; Oxygen/metabolism ; Pancreatic Neoplasms/*blood supply/genetics/*immunology/metabolism ; RGS Proteins/*deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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