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  • 1
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    Alternatively spliced TCR mRNA induced by disruption of reading frame (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-07-06
    Description: Nonsense codons that prematurely terminate translation generate potentially deleterious truncated proteins. Here, we show that the T cell receptor-beta (TCRbeta) gene, which acquires in-frame nonsense codons at high frequency during normal lymphocyte development, gives rise to an alternatively spliced transcript [alternative messenger RNA (alt-mRNA)] that skips the offending mutations that generate such nonsense codons. This alt-mRNA is up-regulated by a transfer RNA-dependent scanning mechanism that responds specifically to mutations that disrupt the reading frame. The finding that translation signals regulate the levels of alternatively spliced mRNAs generated in the nucleus may alter the current view of how gene expression is controlled in eukaryotic cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Jun -- Hamilton, John I -- Carter, Mark S -- Li, Shulin -- Wilkinson, Miles F -- New York, N.Y. -- Science. 2002 Jul 5;297(5578):108-10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, The University of Texas M. D. Anderson Cancer Center, Box 180, 1515 Holcombe Boulevard, Houston, TX 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12098701" target="_blank"〉PubMed〈/a〉
    Keywords: *Alternative Splicing ; Animals ; Cell Nucleus/genetics/metabolism ; *Codon, Nonsense ; Enhancer Elements, Genetic ; Exons ; Frameshift Mutation ; HeLa Cells ; Humans ; Introns ; Mice ; Mutation, Missense ; Protein Biosynthesis ; RNA, Messenger/genetics/metabolism ; *Reading Frames ; Receptors, Antigen, T-Cell, alpha-beta/*genetics ; Up-Regulation
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    Mechanism and regulation of acetylated histone binding by the tandem PHD finger of DPF3b (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-07-09
    Description: Histone lysine acetylation and methylation have an important role during gene transcription in a chromatin context. Knowledge concerning the types of protein modules that can interact with acetyl-lysine has so far been limited to bromodomains. Recently, a tandem plant homeodomain (PHD) finger (PHD1-PHD2, or PHD12) of human DPF3b, which functions in association with the BAF chromatin remodelling complex to initiate gene transcription during heart and muscle development, was reported to bind histones H3 and H4 in an acetylation-sensitive manner, making it the first alternative to bromodomains for acetyl-lysine binding. Here we report the structural mechanism of acetylated histone binding by the double PHD fingers of DPF3b. Our three-dimensional solution structures and biochemical analysis of DPF3b highlight the molecular basis of the integrated tandem PHD finger, which acts as one functional unit in the sequence-specific recognition of lysine-14-acetylated histone H3 (H3K14ac). Whereas the interaction with H3 is promoted by acetylation at lysine 14, it is inhibited by methylation at lysine 4, and these opposing influences are important during transcriptional activation of the mouse DPF3b target genes Pitx2 and Jmjd1c. Binding of this tandem protein module to chromatin can thus be regulated by different histone modifications during the initiation of gene transcription.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2901902/" 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/PMC2901902/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zeng, Lei -- Zhang, Qiang -- Li, Side -- Plotnikov, Alexander N -- Walsh, Martin J -- Zhou, Ming-Ming -- R01 CA087658/CA/NCI NIH HHS/ -- R01 CA087658-10/CA/NCI NIH HHS/ -- R01 HG004508/HG/NHGRI NIH HHS/ -- R01 HG004508-02/HG/NHGRI NIH HHS/ -- England -- Nature. 2010 Jul 8;466(7303):258-62. doi: 10.1038/nature09139.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural and Chemical Biology, Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1677, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20613843" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Cell Line ; DNA-Binding Proteins/*chemistry/genetics/*metabolism ; Histones/*chemistry/*metabolism ; Humans ; Lysine/chemistry/metabolism ; Mice ; Models, Molecular ; Nuclear Magnetic Resonance, Biomolecular ; Protein Folding ; Structure-Activity Relationship ; Substrate Specificity ; Thermodynamics ; Transcription Factors/*chemistry/genetics/*metabolism ; Transcription, Genetic ; Transcriptional Activation ; Up-Regulation ; *Zinc Fingers
    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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  • 3
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    Advanced cardiac morphogenesis does not require heart tube fusion (2004)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2004-09-14
    Description: The bilateral cardiac mesoderm migrates from the lateral region of the embryo to the ventral midline, where it fuses to form the primitive heart tube. It is generally accepted that migration and fusion are essential for subsequent stages of cardiac morphogenesis. We present evidence that, in Foxp4 mutant embryonic mice, each bilateral heart-forming region is capable of developing into a highly differentiated four-chambered mammalian heart in the absence of midline fusion. These data demonstrate that left-right chamber specification, cardiac looping, septation, cardiac myocyte differentiation, and endocardial cushion formation are preprogrammed in the precardiac mesoderm and do not require midline positional identity or heart tube fusion.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Shanru -- Zhou, Deying -- Lu, Min Min -- Morrisey, Edward E -- HL71589/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2004 Sep 10;305(5690):1619-22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15361625" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Atrial Natriuretic Factor/metabolism ; Basic Helix-Loop-Helix Transcription Factors ; Body Patterning ; Cell Differentiation ; DNA-Binding Proteins/genetics/metabolism ; Endocardium/embryology ; Endoderm/cytology/metabolism ; Forkhead Transcription Factors ; Gene Targeting ; Heart/*embryology ; Heart Atria/embryology ; Heart Ventricles/embryology ; In Situ Hybridization ; Mesoderm/physiology ; Mice ; Morphogenesis ; Mutation ; Myocytes, Cardiac/*cytology ; Proto-Oncogene Proteins c-myc/metabolism ; Transcription Factors/metabolism ; Zebrafish Proteins
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-08-21
    Description: The tumour necrosis factor (TNF) family is crucial for immune homeostasis, cell death and inflammation. These cytokines are recognized by members of the TNF receptor (TNFR) family of death receptors, including TNFR1 and TNFR2, and FAS and TNF-related apoptosis-inducing ligand (TRAIL) receptors. Death receptor signalling requires death-domain-mediated homotypic/heterotypic interactions between the receptor and its downstream adaptors, including TNFR1-associated death domain protein (TRADD) and FAS-associated death domain protein (FADD). Here we discover that death domains in several proteins, including TRADD, FADD, RIPK1 and TNFR1, were directly inactivated by NleB, an enteropathogenic Escherichia coli (EPEC) type III secretion system effector known to inhibit host nuclear factor-kappaB (NF-kappaB) signalling. NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase activity that specifically modified a conserved arginine in these death domains (Arg 235 in the TRADD death domain). NleB GlcNAcylation (the addition of GlcNAc onto a protein side chain) of death domains blocked homotypic/heterotypic death domain interactions and assembly of the oligomeric TNFR1 complex, thereby disrupting TNF signalling in EPEC-infected cells, including NF-kappaB signalling, apoptosis and necroptosis. Type-III-delivered NleB also blocked FAS ligand and TRAIL-induced cell death by preventing formation of a FADD-mediated death-inducing signalling complex (DISC). The arginine GlcNAc transferase activity of NleB was required for bacterial colonization in the mouse model of EPEC infection. The mechanism of action of NleB represents a new model by which bacteria counteract host defences, and also a previously unappreciated post-translational modification.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Shan -- Zhang, Li -- Yao, Qing -- Li, Lin -- Dong, Na -- Rong, Jie -- Gao, Wenqing -- Ding, Xiaojun -- Sun, Liming -- Chen, Xing -- Chen, She -- Shao, Feng -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Sep 12;501(7466):242-6. doi: 10.1038/nature12436. Epub 2013 Aug 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉College of Biological Sciences, China Agricultural University, Beijing 100094, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23955153" target="_blank"〉PubMed〈/a〉
    Keywords: Acylation ; Animals ; Antigens, CD95/metabolism ; Apoptosis ; Arginine/*metabolism ; Death Domain Receptor Signaling Adaptor Proteins/metabolism ; Disease Models, Animal ; Enteropathogenic Escherichia coli/*metabolism/pathogenicity ; Escherichia coli Infections/metabolism/microbiology/pathology ; Escherichia coli Proteins/*metabolism ; Fas-Associated Death Domain Protein/chemistry/metabolism ; HeLa Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes/chemistry/metabolism ; N-Acetylglucosaminyltransferases/*metabolism ; NF-kappa B/metabolism ; Protein Biosynthesis ; Protein Structure, Tertiary ; Receptor-Interacting Protein Serine-Threonine Kinases/chemistry/metabolism ; Receptors, Tumor Necrosis Factor, Type I/chemistry/metabolism ; *Signal Transduction ; TNF Receptor-Associated Death Domain Protein/*chemistry/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Virulence ; Virulence Factors/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-07-06
    Description: The adult stem cell marker Lgr5 and its relative Lgr4 are often co-expressed in Wnt-driven proliferative compartments. We find that conditional deletion of both genes in the mouse gut impairs Wnt target gene expression and results in the rapid demise of intestinal crypts, thus phenocopying Wnt pathway inhibition. Mass spectrometry demonstrates that Lgr4 and Lgr5 associate with the Frizzled/Lrp Wnt receptor complex. Each of the four R-spondins, secreted Wnt pathway agonists, can bind to Lgr4, -5 and -6. In HEK293 cells, RSPO1 enhances canonical WNT signals initiated by WNT3A. Removal of LGR4 does not affect WNT3A signalling, but abrogates the RSPO1-mediated signal enhancement, a phenomenon rescued by re-expression of LGR4, -5 or -6. Genetic deletion of Lgr4/5 in mouse intestinal crypt cultures phenocopies withdrawal of Rspo1 and can be rescued by Wnt pathway activation. Lgr5 homologues are facultative Wnt receptor components that mediate Wnt signal enhancement by soluble R-spondin proteins. These results will guide future studies towards the application of R-spondins for regenerative purposes of tissues expressing Lgr5 homologues.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Lau, Wim -- Barker, Nick -- Low, Teck Y -- Koo, Bon-Kyoung -- Li, Vivian S W -- Teunissen, Hans -- Kujala, Pekka -- Haegebarth, Andrea -- Peters, Peter J -- van de Wetering, Marc -- Stange, Daniel E -- van Es, Johan E -- Guardavaccaro, Daniele -- Schasfoort, Richard B M -- Mohri, Yasuaki -- Nishimori, Katsuhiko -- Mohammed, Shabaz -- Heck, Albert J R -- Clevers, Hans -- England -- Nature. 2011 Jul 4;476(7360):293-7. doi: 10.1038/nature10337.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Institute and University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21727895" target="_blank"〉PubMed〈/a〉
    Keywords: Adult Stem Cells/metabolism ; Animals ; Cells, Cultured ; Epithelial Cells/cytology/metabolism ; Frizzled Receptors/metabolism ; Gene Deletion ; HEK293 Cells ; Humans ; Mice ; Protein Binding ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/chemistry/deficiency/genetics/*metabolism ; Regeneration ; *Signal Transduction/genetics ; Thrombospondins/*metabolism ; Wnt Proteins/genetics/*metabolism ; Wnt3 Protein ; Wnt3A Protein
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Novel mutations target distinct subgroups of medulloblastoma (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-06-23
    Description: Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412905/" 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/PMC3412905/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Robinson, Giles -- Parker, Matthew -- Kranenburg, Tanya A -- Lu, Charles -- Chen, Xiang -- Ding, Li -- Phoenix, Timothy N -- Hedlund, Erin -- Wei, Lei -- Zhu, Xiaoyan -- Chalhoub, Nader -- Baker, Suzanne J -- Huether, Robert -- Kriwacki, Richard -- Curley, Natasha -- Thiruvenkatam, Radhika -- Wang, Jianmin -- Wu, Gang -- Rusch, Michael -- Hong, Xin -- Becksfort, Jared -- Gupta, Pankaj -- Ma, Jing -- Easton, John -- Vadodaria, Bhavin -- Onar-Thomas, Arzu -- Lin, Tong -- Li, Shaoyi -- Pounds, Stanley -- Paugh, Steven -- Zhao, David -- Kawauchi, Daisuke -- Roussel, Martine F -- Finkelstein, David -- Ellison, David W -- Lau, Ching C -- Bouffet, Eric -- Hassall, Tim -- Gururangan, Sridharan -- Cohn, Richard -- Fulton, Robert S -- Fulton, Lucinda L -- Dooling, David J -- Ochoa, Kerri -- Gajjar, Amar -- Mardis, Elaine R -- Wilson, Richard K -- Downing, James R -- Zhang, Jinghui -- Gilbertson, Richard J -- P01 CA096832/CA/NCI NIH HHS/ -- P01CA96832/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- P30CA021765/CA/NCI NIH HHS/ -- R01 CA129541/CA/NCI NIH HHS/ -- R01CA129541/CA/NCI NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):43-8. doi: 10.1038/nature11213.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉St Jude Children's Research Hospital, Washington University Pediatric Cancer Genome Project, Memphis, Tennessee 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722829" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CREB-Binding Protein/genetics ; Cadherins/genetics ; Cdh1 Proteins ; Cell Cycle Proteins/deficiency/genetics ; Cell Lineage ; Cerebellar Neoplasms/*classification/*genetics/pathology ; Child ; DEAD-box RNA Helicases/genetics ; DNA Copy Number Variations ; DNA Helicases/genetics ; DNA Mutational Analysis ; Disease Models, Animal ; Genome, Human/genetics ; Genomics ; Hedgehog Proteins/metabolism ; Histone Demethylases/genetics ; Histones/metabolism ; Humans ; Medulloblastoma/*classification/*genetics/pathology ; Methylation ; Mice ; Mutation/*genetics ; Nuclear Proteins/genetics ; Phosphatidylinositol 3-Kinases/genetics ; Transcription Factors/genetics ; Wnt Proteins/metabolism ; beta Catenin/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    In vitro expansion of single Lgr5+ liver stem cells induced by Wnt-driven regeneration (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-01-29
    Description: The Wnt target gene Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5) marks actively dividing stem cells in Wnt-driven, self-renewing tissues such as small intestine and colon, stomach and hair follicles. A three-dimensional culture system allows long-term clonal expansion of single Lgr5(+) stem cells into transplantable organoids (budding cysts) that retain many characteristics of the original epithelial architecture. A crucial component of the culture medium is the Wnt agonist RSPO1, the recently discovered ligand of LGR5. Here we show that Lgr5-lacZ is not expressed in healthy adult liver, however, small Lgr5-LacZ(+) cells appear near bile ducts upon damage, coinciding with robust activation of Wnt signalling. As shown by mouse lineage tracing using a new Lgr5-IRES-creERT2 knock-in allele, damage-induced Lgr5(+) cells generate hepatocytes and bile ducts in vivo. Single Lgr5(+) cells from damaged mouse liver can be clonally expanded as organoids in Rspo1-based culture medium over several months. Such clonal organoids can be induced to differentiate in vitro and to generate functional hepatocytes upon transplantation into Fah(-/-) mice. These findings indicate that previous observations concerning Lgr5(+) stem cells in actively self-renewing tissues can also be extended to damage-induced stem cells in a tissue with a low rate of spontaneous proliferation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3634804/" 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/PMC3634804/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huch, Meritxell -- Dorrell, Craig -- Boj, Sylvia F -- van Es, Johan H -- Li, Vivian S W -- van de Wetering, Marc -- Sato, Toshiro -- Hamer, Karien -- Sasaki, Nobuo -- Finegold, Milton J -- Haft, Annelise -- Vries, Robert G -- Grompe, Markus -- Clevers, Hans -- 104151/Wellcome Trust/United Kingdom -- P30 DK056338/DK/NIDDK NIH HHS/ -- R01 DK051592/DK/NIDDK NIH HHS/ -- England -- Nature. 2013 Feb 14;494(7436):247-50. doi: 10.1038/nature11826. Epub 2013 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Institute for Developmental Biology and Stem Cell Research, University Medical Centre Utrecht, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23354049" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Bile Ducts/cytology/metabolism ; Cell Lineage ; Clone Cells/cytology/metabolism ; Culture Media/chemistry/metabolism ; Disease Models, Animal ; Female ; Gene Knock-In Techniques ; Hepatocytes/*cytology/*metabolism/pathology ; Hydrolases/deficiency/genetics ; Liver/cytology/metabolism/pathology ; Liver Diseases/metabolism/pathology ; Male ; Mice ; Multipotent Stem Cells/cytology/metabolism ; Organoids/cytology/transplantation ; Receptors, G-Protein-Coupled/agonists/deficiency/genetics/*metabolism ; *Regeneration ; Stem Cells/*cytology/*metabolism ; Thrombospondins/deficiency/genetics/metabolism ; Tyrosinemias/metabolism/pathology ; *Wnt Signaling Pathway
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-05
    Description: Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756911/" 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/PMC3756911/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Hong Joo -- Kim, Nam Chul -- Wang, Yong-Dong -- Scarborough, Emily A -- Moore, Jennifer -- Diaz, Zamia -- MacLea, Kyle S -- Freibaum, Brian -- Li, Songqing -- Molliex, Amandine -- Kanagaraj, Anderson P -- Carter, Robert -- Boylan, Kevin B -- Wojtas, Aleksandra M -- Rademakers, Rosa -- Pinkus, Jack L -- Greenberg, Steven A -- Trojanowski, John Q -- Traynor, Bryan J -- Smith, Bradley N -- Topp, Simon -- Gkazi, Athina-Soragia -- Miller, Jack -- Shaw, Christopher E -- Kottlors, Michael -- Kirschner, Janbernd -- Pestronk, Alan -- Li, Yun R -- Ford, Alice Flynn -- Gitler, Aaron D -- Benatar, Michael -- King, Oliver D -- Kimonis, Virginia E -- Ross, Eric D -- Weihl, Conrad C -- Shorter, James -- Taylor, J Paul -- 089701/Wellcome Trust/United Kingdom -- AG031867/AG/NIA NIH HHS/ -- AG032953/AG/NIA NIH HHS/ -- DP2OD002177/OD/NIH HHS/ -- G0900688/Medical Research Council/United Kingdom -- K02 AG042095/AG/NIA NIH HHS/ -- MC_G1000733/Medical Research Council/United Kingdom -- NS053825/NS/NINDS NIH HHS/ -- NS067354/NS/NINDS NIH HHS/ -- P01 AG032953/AG/NIA NIH HHS/ -- R01 AG031867/AG/NIA NIH HHS/ -- R01 NS053825/NS/NINDS NIH HHS/ -- England -- Nature. 2013 Mar 28;495(7442):467-73. doi: 10.1038/nature11922. Epub 2013 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38120, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23455423" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amyotrophic Lateral Sclerosis/*genetics/metabolism/*pathology ; Animals ; Drosophila melanogaster/cytology/genetics/metabolism ; Female ; Frontotemporal Dementia/*genetics/metabolism/pathology ; HeLa Cells ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*chemistry/genetics/*metabolism ; Humans ; Inclusion Bodies/genetics/metabolism/pathology ; Male ; Mice ; Molecular Sequence Data ; Muscular Dystrophies, Limb-Girdle/*genetics/metabolism/pathology ; Mutant Proteins/chemistry/*genetics/metabolism ; Mutation/*genetics ; Myositis, Inclusion Body/*genetics/metabolism/pathology ; Osteitis Deformans/*genetics/metabolism/pathology ; Peptide Termination Factors/chemistry/genetics/metabolism ; Prions/*chemistry/genetics/metabolism ; Protein Structure, Tertiary/genetics ; RNA/metabolism ; Saccharomyces cerevisiae Proteins/chemistry/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    Vaccine activation of the nutrient sensor GCN2 in dendritic cells enhances antigen presentation (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-12-07
    Description: The yellow fever vaccine YF-17D is one of the most successful vaccines ever developed in humans. Despite its efficacy and widespread use in more than 600 million people, the mechanisms by which it stimulates protective immunity remain poorly understood. Recent studies using systems biology approaches in humans have revealed that YF-17D-induced early expression of general control nonderepressible 2 kinase (GCN2) in the blood strongly correlates with the magnitude of the later CD8(+) T cell response. We demonstrate a key role for virus-induced GCN2 activation in programming dendritic cells to initiate autophagy and enhanced antigen presentation to both CD4(+) and CD8(+) T cells. These results reveal an unappreciated link between virus-induced integrated stress response in dendritic cells and the adaptive immune response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048998/" 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/PMC4048998/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ravindran, Rajesh -- Khan, Nooruddin -- Nakaya, Helder I -- Li, Shuzhao -- Loebbermann, Jens -- Maddur, Mohan S -- Park, Youngja -- Jones, Dean P -- Chappert, Pascal -- Davoust, Jean -- Weiss, David S -- Virgin, Herbert W -- Ron, David -- Pulendran, Bali -- 084812/Wellcome Trust/United Kingdom -- 084812/Z/08/Z/Wellcome Trust/United Kingdom -- N01 AI50019/AI/NIAID NIH HHS/ -- N01 AI50025/AI/NIAID NIH HHS/ -- P51 OD011132/OD/NIH HHS/ -- R37 AI048638/AI/NIAID NIH HHS/ -- R37 DK057665/DK/NIDDK NIH HHS/ -- R56 AI048638/AI/NIAID NIH HHS/ -- U19 AI057266/AI/NIAID NIH HHS/ -- U19 AI090023/AI/NIAID NIH HHS/ -- U54 AI057157/AI/NIAID NIH HHS/ -- U54 AI057160/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 17;343(6168):313-7. doi: 10.1126/science.1246829. Epub 2013 Dec 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24310610" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Antigen Presentation ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Line ; Cricetinae ; Dendritic Cells/enzymology/*immunology ; Enzyme Activation ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Microtubule-Associated Proteins/genetics ; Protein-Serine-Threonine Kinases/*biosynthesis/genetics ; Yellow Fever Vaccine/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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    Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-22
    Description: Nucleoside reverse transcriptase inhibitors (NRTIs) are mainstay therapeutics for HIV that block retrovirus replication. Alu (an endogenous retroelement that also requires reverse transcriptase for its life cycle)-derived RNAs activate P2X7 and the NLRP3 inflammasome to cause cell death of the retinal pigment epithelium in geographic atrophy, a type of age-related macular degeneration. We found that NRTIs inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented caspase-1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Our findings suggest that NRTIs are ripe for drug repurposing in P2X7-driven diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274127/" 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/PMC4274127/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fowler, Benjamin J -- Gelfand, Bradley D -- Kim, Younghee -- Kerur, Nagaraj -- Tarallo, Valeria -- Hirano, Yoshio -- Amarnath, Shoba -- Fowler, Daniel H -- Radwan, Marta -- Young, Mark T -- Pittman, Keir -- Kubes, Paul -- Agarwal, Hitesh K -- Parang, Keykavous -- Hinton, David R -- Bastos-Carvalho, Ana -- Li, Shengjian -- Yasuma, Tetsuhiro -- Mizutani, Takeshi -- Yasuma, Reo -- Wright, Charles -- Ambati, Jayakrishna -- BB/J017345/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- DP1 GM114862/GM/NIGMS NIH HHS/ -- DP1GM114862/DP/NCCDPHP CDC HHS/ -- K99 EY024336/EY/NEI NIH HHS/ -- K99EY024336/EY/NEI NIH HHS/ -- P30EY003040/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY020672/EY/NEI NIH HHS/ -- R01 EY022238/EY/NEI NIH HHS/ -- R01 EY024068/EY/NEI NIH HHS/ -- R01EY001545/EY/NEI NIH HHS/ -- R01EY018350/EY/NEI NIH HHS/ -- R01EY018836/EY/NEI NIH HHS/ -- R01EY020672/EY/NEI NIH HHS/ -- R01EY022238/EY/NEI NIH HHS/ -- R01EY024068/EY/NEI NIH HHS/ -- T32HL091812/HL/NHLBI NIH HHS/ -- TL1 RR033172/RR/NCRR NIH HHS/ -- TL1 TR000115/TR/NCATS NIH HHS/ -- UL1 RR033173/RR/NCRR NIH HHS/ -- UL1 TR000117/TR/NCATS NIH HHS/ -- UL1RR033173/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2014 Nov 21;346(6212):1000-3. doi: 10.1126/science.1261754.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Microbiology, Immunology, and Human Genetics, University of Kentucky, Lexington, KY 40536, USA. Department of Biomedical Engineering, University of Kentucky, Lexington, KY 40536, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Angiogenesis Lab, Institute of Genetics and Biophysics, CNR, Naples, Italy. ; Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. ; School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK. ; Immunology Research Group, University of Calgary, Calgary, Alberta T2N 4N1, Canada. ; Chapman University School of Pharmacy, 9401 Jeronimo Road, Harry and Diane Rinker Health Science Campus, Irvine, CA 92618, USA. ; Departments of Pathology and Ophthalmology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536, USA. Department of Physiology, University of Kentucky, Lexington, KY 40536, USA. jamba2@email.uky.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25414314" target="_blank"〉PubMed〈/a〉
    Keywords: Alu Elements ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*pharmacology/therapeutic use ; Apoptosis/drug effects ; Carrier Proteins/metabolism ; Caspase 1/metabolism ; Choroidal Neovascularization/drug therapy ; Disease Models, Animal ; Geographic Atrophy/drug therapy ; Graft vs Host Disease/drug therapy ; Hepatitis/drug therapy ; Inflammasomes/*drug effects ; Liver/drug effects ; Mice ; Receptors, Purinergic P2X7/metabolism ; Retinal Pigment Epithelium/drug effects/metabolism/physiology ; Reverse Transcriptase Inhibitors/*pharmacology/therapeutic use
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
    Location Call Number Expected Availability
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