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  • Articles  (16)
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  • Nature Publishing Group (NPG)  (16)
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  • 1
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    DNA sequencing of a cytogenetically normal acute myeloid leukaemia genome (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-11-07
    Description: Acute myeloid leukaemia is a highly malignant haematopoietic tumour that affects about 13,000 adults in the United States each year. The treatment of this disease has changed little in the past two decades, because most of the genetic events that initiate the disease remain undiscovered. Whole-genome sequencing is now possible at a reasonable cost and timeframe to use this approach for the unbiased discovery of tumour-specific somatic mutations that alter the protein-coding genes. Here we present the results obtained from sequencing a typical acute myeloid leukaemia genome, and its matched normal counterpart obtained from the same patient's skin. We discovered ten genes with acquired mutations; two were previously described mutations that are thought to contribute to tumour progression, and eight were new mutations present in virtually all tumour cells at presentation and relapse, the function of which is not yet known. Our study establishes whole-genome sequencing as an unbiased method for discovering cancer-initiating mutations in previously unidentified genes that may respond to targeted therapies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2603574/" 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/PMC2603574/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ley, Timothy J -- Mardis, Elaine R -- Ding, Li -- Fulton, Bob -- McLellan, Michael D -- Chen, Ken -- Dooling, David -- Dunford-Shore, Brian H -- McGrath, Sean -- Hickenbotham, Matthew -- Cook, Lisa -- Abbott, Rachel -- Larson, David E -- Koboldt, Dan C -- Pohl, Craig -- Smith, Scott -- Hawkins, Amy -- Abbott, Scott -- Locke, Devin -- Hillier, Ladeana W -- Miner, Tracie -- Fulton, Lucinda -- Magrini, Vincent -- Wylie, Todd -- Glasscock, Jarret -- Conyers, Joshua -- Sander, Nathan -- Shi, Xiaoqi -- Osborne, John R -- Minx, Patrick -- Gordon, David -- Chinwalla, Asif -- Zhao, Yu -- Ries, Rhonda E -- Payton, Jacqueline E -- Westervelt, Peter -- Tomasson, Michael H -- Watson, Mark -- Baty, Jack -- Ivanovich, Jennifer -- Heath, Sharon -- Shannon, William D -- Nagarajan, Rakesh -- Walter, Matthew J -- Link, Daniel C -- Graubert, Timothy A -- DiPersio, John F -- Wilson, Richard K -- U54 HG002042/HG/NHGRI NIH HHS/ -- U54 HG002042-05/HG/NHGRI NIH HHS/ -- England -- Nature. 2008 Nov 6;456(7218):66-72. doi: 10.1038/nature07485.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63108, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18987736" target="_blank"〉PubMed〈/a〉
    Keywords: Case-Control Studies ; Disease Progression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/*genetics ; Genome, Human/*genetics ; Genomics ; Humans ; Leukemia, Myeloid, Acute/*genetics ; Mutagenesis, Insertional ; Mutation ; Polymorphism, Single Nucleotide ; Recurrence ; Sequence Analysis, DNA ; Sequence Deletion ; Skin/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    Membrane-bound Fas ligand only is essential for Fas-induced apoptosis (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-10-02
    Description: Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice and humans. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding. Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL (FasL(Deltas/Deltas)) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasL(Deltam/Deltam)) could not kill cells through Fas activation. FasL(Deltam/Deltam) mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL(gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL(Deltam/Deltam) mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL(gld/gld) mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785124/" 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/PMC2785124/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O' Reilly, Lorraine A -- Tai, Lin -- Lee, Lily -- Kruse, Elizabeth A -- Grabow, Stephanie -- Fairlie, W Douglas -- Haynes, Nicole M -- Tarlinton, David M -- Zhang, Jian-Guo -- Belz, Gabrielle T -- Smyth, Mark J -- Bouillet, Philippe -- Robb, Lorraine -- Strasser, Andreas -- CA043540-18/CA/NCI NIH HHS/ -- CA80188-6/CA/NCI NIH HHS/ -- R01 CA043540/CA/NCI NIH HHS/ -- R01 CA043540-18/CA/NCI NIH HHS/ -- R01 CA080188-06/CA/NCI NIH HHS/ -- England -- Nature. 2009 Oct 1;461(7264):659-63. doi: 10.1038/nature08402.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794494" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Antinuclear/immunology ; Antigens, CD95/*metabolism ; *Apoptosis ; Cell Membrane/*metabolism ; Cytidine Deaminase/metabolism ; Cytotoxicity, Immunologic ; Fas Ligand Protein/deficiency/genetics/*metabolism/secretion ; Glomerulonephritis/metabolism ; Histiocytic Sarcoma/metabolism ; Hypergammaglobulinemia/metabolism ; Lupus Erythematosus, Systemic/metabolism ; Lymphatic Diseases/metabolism ; Mice ; Mice, Inbred C57BL ; Mutation ; Splenomegaly/metabolism ; T-Lymphocytes/immunology/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Crystal structure of the anti-viral APOBEC3G catalytic domain and functional implications (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-10-14
    Description: The APOBEC family members are involved in diverse biological functions. APOBEC3G restricts the replication of human immunodeficiency virus (HIV), hepatitis B virus and retroelements by cytidine deamination on single-stranded DNA or by RNA binding. Here we report the high-resolution crystal structure of the carboxy-terminal deaminase domain of APOBEC3G (APOBEC3G-CD2) purified from Escherichia coli. The APOBEC3G-CD2 structure has a five-stranded beta-sheet core that is common to all known deaminase structures and closely resembles the structure of another APOBEC protein, APOBEC2 (ref. 5). A comparison of APOBEC3G-CD2 with other deaminase structures shows a structural conservation of the active-site loops that are directly involved in substrate binding. In the X-ray structure, these APOBEC3G active-site loops form a continuous 'substrate groove' around the active centre. The orientation of this putative substrate groove differs markedly (by 90 degrees) from the groove predicted by the NMR structure. We have introduced mutations around the groove, and have identified residues involved in substrate specificity, single-stranded DNA binding and deaminase activity. These results provide a basis for understanding the underlying mechanisms of substrate specificity for the APOBEC family.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2714533/" 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/PMC2714533/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Holden, Lauren G -- Prochnow, Courtney -- Chang, Y Paul -- Bransteitter, Ronda -- Chelico, Linda -- Sen, Udayaditya -- Stevens, Raymond C -- Goodman, Myron F -- Chen, Xiaojiang S -- R01 AI055926/AI/NIAID NIH HHS/ -- R01 AI055926-05/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Nov 6;456(7218):121-4. doi: 10.1038/nature07357. Epub 2008 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular and Computational Biology, University of Southern California, Los Angeles, California 90089, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18849968" target="_blank"〉PubMed〈/a〉
    Keywords: Antiviral Agents ; *Catalytic Domain ; Crystallography, X-Ray ; Cytidine Deaminase/*chemistry/genetics/isolation & purification/*metabolism ; DNA, Single-Stranded/metabolism ; Escherichia coli ; Humans ; Models, Molecular ; Muscle Proteins/chemistry ; Mutant Proteins/chemistry/genetics/metabolism ; Mutation ; Nuclear Magnetic Resonance, Biomolecular ; Protein Structure, Secondary ; Structural Homology, Protein ; Structure-Activity Relationship ; Substrate Specificity
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  • 4
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    Structural insight into the autoinhibition mechanism of AMP-activated protein kinase (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-05-29
    Description: The AMP-activated protein kinase (AMPK) is characterized by its ability to bind to AMP, which enables it to adjust enzymatic activity by sensing the cellular energy status and maintain the balance between ATP production and consumption in eukaryotic cells. It also has important roles in the regulation of cell growth and proliferation, and in the establishment and maintenance of cell polarity. These important functions have rendered AMPK an important drug target for obesity, type 2 diabetes and cancer treatments. However, the regulatory mechanism of AMPK activity by AMP binding remains unsolved. Here we report the crystal structures of an unphosphorylated fragment of the AMPK alpha-subunit (KD-AID) from Schizosaccharomyces pombe that contains both the catalytic kinase domain and an autoinhibitory domain (AID), and of a phosphorylated kinase domain from Saccharomyces cerevisiae (Snf1-pKD). The AID binds, from the 'backside', to the hinge region of its kinase domain, forming contacts with both amino-terminal and carboxy-terminal lobes. Structural analyses indicate that AID binding might constrain the mobility of helix alphaC, hence resulting in an autoinhibited KD-AID with much lower kinase activity than that of the kinase domain alone. AMP activates AMPK both allosterically and by inhibiting dephosphorylation. Further in vitro kinetic studies demonstrate that disruption of the KD-AID interface reverses the autoinhibition and these AMPK heterotrimeric mutants no longer respond to the change in AMP concentration. The structural and biochemical data have shown the primary mechanism of AMPK autoinhibition and suggest a conformational switch model for AMPK activation by AMP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Lei -- Jiao, Zhi-Hao -- Zheng, Li-Sha -- Zhang, Yuan-Yuan -- Xie, Shu-Tao -- Wang, Zhi-Xin -- Wu, Jia-Wei -- England -- Nature. 2009 Jun 25;459(7250):1146-9. doi: 10.1038/nature08075. Epub 2009 May 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MOE Key Laboratory of Bioinformatics, Department of Biological Sciences and Biotechnology, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19474788" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/*chemistry/*metabolism ; Adenosine Monophosphate/metabolism ; Amino Acid Sequence ; Animals ; *Models, Molecular ; Molecular Sequence Data ; Mutation ; Phosphorylation ; Protein Structure, Tertiary ; Rats ; Saccharomyces cerevisiae/*enzymology ; Schizosaccharomyces/*enzymology ; Sequence Alignment
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  • 5
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    Structure and function of the 5'--〉3' exoribonuclease Rat1 and its activating partner Rai1 (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-02-06
    Description: The 5'--〉3' exoribonucleases (XRNs) comprise a large family of conserved enzymes in eukaryotes with crucial functions in RNA metabolism and RNA interference. XRN2, or Rat1 in yeast, functions primarily in the nucleus and also has an important role in transcription termination by RNA polymerase II (refs 7-14). Rat1 exoribonuclease activity is stimulated by the protein Rai1 (refs 15, 16). Here we report the crystal structure at 2.2 A resolution of Schizosaccharomyces pombe Rat1 in complex with Rai1, as well as the structures of Rai1 and its murine homologue Dom3Z alone at 2.0 A resolution. The structures reveal the molecular mechanism for the activation of Rat1 by Rai1 and for the exclusive exoribonuclease activity of Rat1. Biochemical studies confirm these observations, and show that Rai1 allows Rat1 to degrade RNAs with stable secondary structure more effectively. There are large differences in the active site landscape of Rat1 compared to related and PIN (PilT N terminus) domain-containing nucleases. Unexpectedly, we identified a large pocket in Rai1 and Dom3Z that contains highly conserved residues, including three acidic side chains that coordinate a divalent cation. Mutagenesis and biochemical studies demonstrate that Rai1 possesses pyrophosphohydrolase activity towards 5' triphosphorylated RNA. Such an activity is important for messenger RNA degradation in bacteria, but this is, to our knowledge, the first demonstration of this activity in eukaryotes and suggests that Rai1/Dom3Z may have additional important functions in RNA metabolism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739979/" 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/PMC2739979/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xiang, Song -- Cooper-Morgan, Amalene -- Jiao, Xinfu -- Kiledjian, Megerditch -- Manley, James L -- Tong, Liang -- GM077175/GM/NIGMS NIH HHS/ -- GM28983/GM/NIGMS NIH HHS/ -- GM67005/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 GM067005/GM/NIGMS NIH HHS/ -- R01 GM067005-01A2/GM/NIGMS NIH HHS/ -- R01 GM077175/GM/NIGMS NIH HHS/ -- R01 GM077175-02/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Apr 9;458(7239):784-8. doi: 10.1038/nature07731. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Columbia University, New York, New York 10027, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194460" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Exoribonucleases/*chemistry/genetics/*metabolism ; Mice ; *Models, Molecular ; Mutation ; *Nuclear Proteins/chemistry/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Recombinant Proteins/chemistry/metabolism ; *Schizosaccharomyces/chemistry/enzymology/genetics ; Schizosaccharomyces pombe Proteins/*chemistry/genetics/*metabolism
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  • 6
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    Control of plant germline proliferation by SCF(FBL17) degradation of cell cycle inhibitors (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-10-25
    Description: Flowering plants possess a unique reproductive strategy, involving double fertilization by twin sperm cells. Unlike animal germ lines, the male germ cell lineage in plants only forms after meiosis and involves asymmetric division of haploid microspores, to produce a large, non-germline vegetative cell and a germ cell that undergoes one further division to produce the twin sperm cells. Although this switch in cell cycle control is critical for sperm cell production and delivery, the underlying molecular mechanisms are unknown. Here we identify a novel F-box protein of Arabidopsis thaliana, designated FBL17 (F-box-like 17), that enables this switch by targeting the degradation of cyclin-dependent kinase A;1 inhibitors specifically in male germ cells. We show that FBL17 is transiently expressed in the male germ line after asymmetric division and forms an SKP1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase complex (SCF(FBL17)) that targets the cyclin-dependent kinase inhibitors KRP6 and KRP7 for proteasome-dependent degradation. Accordingly, the loss of FBL17 function leads to the stabilization of KRP6 and inhibition of germ cell cycle progression. Our results identify SCF(FBL17) as an essential male germ cell proliferation complex that promotes twin sperm cell production and double fertilization in flowering plants.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Hyo Jung -- Oh, Sung Aeong -- Brownfield, Lynette -- Hong, Sung Hyun -- Ryu, Hojin -- Hwang, Ildoo -- Twell, David -- Nam, Hong Gil -- BB/C004205/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2008 Oct 23;455(7216):1134-7. doi: 10.1038/nature07289.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Life Sciences, Pohang University of Science and Technology, Pohang 790-784, South Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18948957" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*cytology/embryology/genetics/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Cell Cycle/*physiology ; Cell Division/genetics ; Cell Proliferation ; Cyclin-Dependent Kinase Inhibitor Proteins/*metabolism ; F-Box Proteins/genetics/*metabolism ; Gene Expression Regulation, Plant ; Mutation ; Pollen/*cytology ; Proteasome Endopeptidase Complex/metabolism ; SKP Cullin F-Box Protein Ligases/metabolism
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  • 7
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    UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-02-29
    Description: Signalling by means of toll-like receptors (TLRs) is essential for the development of innate and adaptive immune responses. UNC93B1, essential for signalling of TLR3, TLR7 and TLR9 in both humans and mice, physically interacts with these TLRs in the endoplasmic reticulum (ER). Here we show that the function of the polytopic membrane protein UNC93B1 is to deliver the nucleotide-sensing receptors TLR7 and TLR9 from the ER to endolysosomes. In dendritic cells of 3d mice, which express an UNC93B1 missense mutant (H412R) incapable of TLR binding, neither TLR7 nor TLR9 exits the ER. Furthermore, the trafficking and signalling defects of the nucleotide-sensing TLRs in 3d dendritic cells are corrected by expression of wild-type UNC93B1. However, UNC93B1 is dispensable for ligand recognition and signal initiation by TLRs. To our knowledge, UNC93B1 is the first protein to be identified as a molecule specifically involved in trafficking of nucleotide-sensing TLRs. By inhibiting the interaction between UNC93B1 and TLRs it should be possible to achieve specific regulation of the nucleotide-sensing TLRs without compromising signalling via the cell-surface-disposed TLRs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, You-Me -- Brinkmann, Melanie M -- Paquet, Marie-Eve -- Ploegh, Hidde L -- England -- Nature. 2008 Mar 13;452(7184):234-8. doi: 10.1038/nature06726. Epub 2008 Feb 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA. ykim@wi.mit.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18305481" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Dendritic Cells/metabolism ; *Endocytosis ; Endoplasmic Reticulum/metabolism ; Humans ; Ligands ; Lysosomes/*metabolism ; Membrane Glycoproteins/*metabolism ; Membrane Transport Proteins/chemistry/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mutation ; Nucleotides/*metabolism ; Protein Transport ; Signal Transduction ; Toll-Like Receptor 7/*metabolism ; Toll-Like Receptor 9/*metabolism
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  • 8
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    Coordinate control of synaptic-layer specificity and rhodopsins in photoreceptor neurons (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-11-04
    Description: How neurons make specific synaptic connections is a central question in neurobiology. The targeting of the Drosophila R7 and R8 photoreceptor axons to different synaptic layers in the brain provides a model with which to explore the genetic programs regulating target specificity. In principle this can be accomplished by cell-type-specific molecules mediating the recognition between synaptic partners. Alternatively, specificity could also be achieved through cell-type-specific repression of particular targeting molecules. Here we show that a key step in the targeting of the R7 neuron is the active repression of the R8 targeting program. Repression is dependent on NF-YC, a subunit of the NF-Y (nuclear factor Y) transcription factor. In the absence of NF-YC, R7 axons terminate in the same layer as R8 axons. Genetic experiments indicate that this is due solely to the derepression of the R8-specific transcription factor Senseless (Sens) late in R7 differentiation. Sens is sufficient to control R8 targeting specificity and we demonstrate that Sens directly binds to an evolutionarily conserved DNA sequence upstream of the start of transcription of an R8-specific cell-surface protein, Capricious (Caps) that regulates R8 target specificity. We show that R7 targeting requires the R7-specific transcription factor Prospero (Pros) in parallel to repression of the R8 targeting pathway by NF-YC. Previous studies demonstrated that Sens and Pros directly regulate the expression of specific rhodopsins in R8 and R7. We propose that the use of the same transcription factors to promote the cell-type-specific expression of sensory receptors and cell-surface proteins regulating synaptic target specificity provides a simple and general mechanism for ensuring that transmission of sensory information is processed by the appropriate specialized neural circuits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727603/" 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/PMC2727603/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morey, Marta -- Yee, Susan K -- Herman, Tory -- Nern, Aljoscha -- Blanco, Enrique -- Zipursky, S Lawrence -- GM7185/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Dec 11;456(7223):795-9. doi: 10.1038/nature07419.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry, Howard Hughes Medical Institute, David Geffen School of Medicine, 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/18978774" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Compound Eye, Arthropod/growth & development/metabolism ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/genetics/*physiology ; *Gene Expression Regulation, Developmental ; Membrane Proteins/metabolism ; Mutation ; Nerve Tissue Proteins/metabolism ; Nuclear Proteins/genetics/metabolism ; Photoreceptor Cells, Invertebrate/physiology ; Rhodopsin/*metabolism ; Substrate Specificity ; Synapses/*metabolism ; Transcription Factors/genetics/metabolism
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  • 9
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    A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-10-14
    Description: Susceptibility to Crohn's disease, a complex inflammatory disease involving the small intestine, is controlled by over 30 loci. One Crohn's disease risk allele is in ATG16L1, a gene homologous to the essential yeast autophagy gene ATG16 (ref. 2). It is not known how ATG16L1 or autophagy contributes to intestinal biology or Crohn's disease pathogenesis. To address these questions, we generated and characterized mice that are hypomorphic for ATG16L1 protein expression, and validated conclusions on the basis of studies in these mice by analysing intestinal tissues that we collected from Crohn's disease patients carrying the Crohn's disease risk allele of ATG16L1. Here we show that ATG16L1 is a bona fide autophagy protein. Within the ileal epithelium, both ATG16L1 and a second essential autophagy protein ATG5 are selectively important for the biology of the Paneth cell, a specialized epithelial cell that functions in part by secretion of granule contents containing antimicrobial peptides and other proteins that alter the intestinal environment. ATG16L1- and ATG5-deficient Paneth cells exhibited notable abnormalities in the granule exocytosis pathway. In addition, transcriptional analysis revealed an unexpected gain of function specific to ATG16L1-deficient Paneth cells including increased expression of genes involved in peroxisome proliferator-activated receptor (PPAR) signalling and lipid metabolism, of acute phase reactants and of two adipocytokines, leptin and adiponectin, known to directly influence intestinal injury responses. Importantly, Crohn's disease patients homozygous for the ATG16L1 Crohn's disease risk allele displayed Paneth cell granule abnormalities similar to those observed in autophagy-protein-deficient mice and expressed increased levels of leptin protein. Thus, ATG16L1, and probably the process of autophagy, have a role within the intestinal epithelium of mice and Crohn's disease patients by selective effects on the cell biology and specialized regulatory properties of Paneth cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695978/" 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/PMC2695978/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cadwell, Ken -- Liu, John Y -- Brown, Sarah L -- Miyoshi, Hiroyuki -- Loh, Joy -- Lennerz, Jochen K -- Kishi, Chieko -- Kc, Wumesh -- Carrero, Javier A -- Hunt, Steven -- Stone, Christian D -- Brunt, Elizabeth M -- Xavier, Ramnik J -- Sleckman, Barry P -- Li, Ellen -- Mizushima, Noboru -- Stappenbeck, Thaddeus S -- Virgin, Herbert W 4th -- AI062773/AI/NIAID NIH HHS/ -- DK43351/DK/NIDDK NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-13/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- P30 DK043351-18/DK/NIDDK NIH HHS/ -- P30 DK052574-09/DK/NIDDK NIH HHS/ -- P30 DK52574/DK/NIDDK NIH HHS/ -- R01 AI062773/AI/NIAID NIH HHS/ -- R01 AI062773-01A1/AI/NIAID NIH HHS/ -- R01 AI062832/AI/NIAID NIH HHS/ -- R01 AI062832-04/AI/NIAID NIH HHS/ -- T32 AR007279/AR/NIAMS NIH HHS/ -- T32 AR007279-30/AR/NIAMS NIH HHS/ -- T32 AR07279/AR/NIAMS NIH HHS/ -- U54 AI057160/AI/NIAID NIH HHS/ -- U54 AI057160-010005/AI/NIAID NIH HHS/ -- U54 AI057160-05S10018/AI/NIAID NIH HHS/ -- England -- Nature. 2008 Nov 13;456(7219):259-63. doi: 10.1038/nature07416. Epub 2008 Oct 5.〈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/18849966" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Autophagy/*genetics ; Carrier Proteins/genetics/*metabolism ; Cell Line ; Crohn Disease/genetics/pathology ; Exocytosis/genetics ; Homozygote ; Humans ; Mice ; Mice, Inbred C57BL ; Mutation ; Paneth Cells/*metabolism/pathology
    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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  • 10
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    Histone H4 lysine 16 acetylation regulates cellular lifespan (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-06-12
    Description: Cells undergoing developmental processes are characterized by persistent non-genetic alterations in chromatin, termed epigenetic changes, represented by distinct patterns of DNA methylation and histone post-translational modifications. Sirtuins, a group of conserved NAD(+)-dependent deacetylases or ADP-ribosyltransferases, promote longevity in diverse organisms; however, their molecular mechanisms in ageing regulation remain poorly understood. Yeast Sir2, the first member of the family to be found, establishes and maintains chromatin silencing by removing histone H4 lysine 16 acetylation and bringing in other silencing proteins. Here we report an age-associated decrease in Sir2 protein abundance accompanied by an increase in H4 lysine 16 acetylation and loss of histones at specific subtelomeric regions in replicatively old yeast cells, which results in compromised transcriptional silencing at these loci. Antagonizing activities of Sir2 and Sas2, a histone acetyltransferase, regulate the replicative lifespan through histone H4 lysine 16 at subtelomeric regions. This pathway, distinct from existing ageing models for yeast, may represent an evolutionarily conserved function of sirtuins in regulation of replicative ageing by maintenance of intact telomeric chromatin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2702157/" 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/PMC2702157/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dang, Weiwei -- Steffen, Kristan K -- Perry, Rocco -- Dorsey, Jean A -- Johnson, F Brad -- Shilatifard, Ali -- Kaeberlein, Matt -- Kennedy, Brian K -- Berger, Shelley L -- R01 AG025549/AG/NIA NIH HHS/ -- R01 AG025549-01A2/AG/NIA NIH HHS/ -- R01 AG025549-03/AG/NIA NIH HHS/ -- R01 CA089455/CA/NCI NIH HHS/ -- England -- Nature. 2009 Jun 11;459(7248):802-7. doi: 10.1038/nature08085.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression and Regulation Program, The Wistar Institute Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19516333" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Acetyltransferases/metabolism ; Cell Division ; Chromatin/genetics/metabolism ; Epistasis, Genetic ; Gene Expression Regulation, Fungal ; Gene Silencing ; Histone Acetyltransferases ; Histone Deacetylase Inhibitors ; Histone Deacetylases/deficiency/metabolism ; Histones/*chemistry/genetics/*metabolism ; Lysine/*metabolism ; Mutant Proteins/genetics/metabolism ; Mutation ; Saccharomyces cerevisiae/*cytology/genetics/*metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Silent Information Regulator Proteins, Saccharomyces cerevisiae/antagonists & ; inhibitors/deficiency/metabolism ; Sirtuin 2 ; Sirtuins/antagonists & inhibitors/deficiency/metabolism ; Telomere/genetics/metabolism ; Transcription, Genetic
    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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