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  • 1
    Publication Date: 2004-02-21
    Description: The Sir2 deacetylase modulates organismal life-span in various species. However, the molecular mechanisms by which Sir2 increases longevity are largely unknown. We show that in mammalian cells, the Sir2 homolog SIRT1 appears to control the cellular response to stress by regulating the FOXO family of Forkhead transcription factors, a family of proteins that function as sensors of the insulin signaling pathway and as regulators of organismal longevity. SIRT1 and the FOXO transcription factor FOXO3 formed a complex in cells in response to oxidative stress, and SIRT1 deacetylated FOXO3 in vitro and within cells. SIRT1 had a dual effect on FOXO3 function: SIRT1 increased FOXO3's ability to induce cell cycle arrest and resistance to oxidative stress but inhibited FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brunet, Anne -- Sweeney, Lora B -- Sturgill, J Fitzhugh -- Chua, Katrin F -- Greer, Paul L -- Lin, Yingxi -- Tran, Hien -- Ross, Sarah E -- Mostoslavsky, Raul -- Cohen, Haim Y -- Hu, Linda S -- Cheng, Hwei-Ling -- Jedrychowski, Mark P -- Gygi, Steven P -- Sinclair, David A -- Alt, Frederick W -- Greenberg, Michael E -- NIHP30-HD18655/HD/NICHD NIH HHS/ -- P01 NS35138-17/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2004 Mar 26;303(5666):2011-5. Epub 2004 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Neuroscience, Children's Hospital, and Department of Neurobiology, Center for Blood Research (CBR) Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/14976264" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Apoptosis ; Cell Cycle ; Cell Line ; Cell Nucleus/metabolism ; Cells, Cultured ; Cerebellum/cytology ; Forkhead Transcription Factors ; Gene Expression Profiling ; Gene Expression Regulation ; Histone Deacetylases/genetics/*metabolism ; Humans ; Intracellular Signaling Peptides and Proteins ; Mice ; Mice, Knockout ; Neurons/cytology ; *Oxidative Stress ; Phosphorylation ; Proteins/genetics ; Recombinant Proteins/metabolism ; Sirtuin 1 ; Sirtuins/genetics/*metabolism ; Transcription Factors/genetics/*metabolism ; Transcription, Genetic
    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
    Publication Date: 2011-04-19
    Description: Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598045/" 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/PMC4598045/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guarani, Virginia -- Deflorian, Gianluca -- Franco, Claudio A -- Kruger, Marcus -- Phng, Li-Kun -- Bentley, Katie -- Toussaint, Louise -- Dequiedt, Franck -- Mostoslavsky, Raul -- Schmidt, Mirko H H -- Zimmermann, Barbara -- Brandes, Ralf P -- Mione, Marina -- Westphal, Christoph H -- Braun, Thomas -- Zeiher, Andreas M -- Gerhardt, Holger -- Dimmeler, Stefanie -- Potente, Michael -- R01 DK088190/DK/NIDDK NIH HHS/ -- R01 GM093072/GM/NIGMS NIH HHS/ -- R01DK088190-01A1/DK/NIDDK NIH HHS/ -- R01GM093072-01/GM/NIGMS NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 May 12;473(7346):234-8. doi: 10.1038/nature09917. Epub 2011 Apr 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, D-60590 Frankfurt, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21499261" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Endothelial Cells/cytology/*enzymology ; *Gene Expression Regulation ; Gene Knockout Techniques ; Gene Silencing ; HEK293 Cells ; Humans ; Mice ; Mutation ; Receptor, Notch1/metabolism ; Receptors, Notch/*metabolism ; Signal Transduction/*physiology ; Sirtuin 1/*genetics/*metabolism ; Zebrafish/embryology/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2013-04-05
    Description: The Sir2 family of enzymes or sirtuins are known as nicotinamide adenine dinucleotide (NAD)-dependent deacetylases and have been implicated in the regulation of transcription, genome stability, metabolism and lifespan. However, four of the seven mammalian sirtuins have very weak deacetylase activity in vitro. Here we show that human SIRT6 efficiently removes long-chain fatty acyl groups, such as myristoyl, from lysine residues. The crystal structure of SIRT6 reveals a large hydrophobic pocket that can accommodate long-chain fatty acyl groups. We demonstrate further that SIRT6 promotes the secretion of tumour necrosis factor-alpha (TNF-alpha) by removing the fatty acyl modification on K19 and K20 of TNF-alpha. Protein lysine fatty acylation has been known to occur in mammalian cells, but the function and regulatory mechanisms of this modification were unknown. Our data indicate that protein lysine fatty acylation is a novel mechanism that regulates protein secretion. The discovery of SIRT6 as an enzyme that controls protein lysine fatty acylation provides new opportunities to investigate the physiological function of a protein post-translational modification that has been little studied until now.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635073/" 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/PMC3635073/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Hong -- Khan, Saba -- Wang, Yi -- Charron, Guillaume -- He, Bin -- Sebastian, Carlos -- Du, Jintang -- Kim, Ray -- Ge, Eva -- Mostoslavsky, Raul -- Hang, Howard C -- Hao, Quan -- Lin, Hening -- R01 CA175727/CA/NCI NIH HHS/ -- R01 DK088190/DK/NIDDK NIH HHS/ -- R01 GM086703/GM/NIGMS NIH HHS/ -- R01 GM087544/GM/NIGMS NIH HHS/ -- R01 GM093072/GM/NIGMS NIH HHS/ -- R01GM086703/GM/NIGMS NIH HHS/ -- R01GM087544/GM/NIGMS NIH HHS/ -- R01GM093072/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Apr 4;496(7443):110-3. doi: 10.1038/nature12038.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23552949" target="_blank"〉PubMed〈/a〉
    Keywords: Acylation ; Binding Sites ; Crystallography, X-Ray ; Fatty Acids/*chemistry/*metabolism ; Humans ; Hydrolysis ; Hydrophobic and Hydrophilic Interactions ; Lysine/*analogs & derivatives/chemistry/*metabolism ; Protein Processing, Post-Translational ; Sirtuins/chemistry/*metabolism ; Tumor Necrosis Factor-alpha/chemistry/metabolism/*secretion
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2009-07-31
    Description: The sirtuins are a highly conserved family of NAD(+)-dependent enzymes that regulate lifespan in lower organisms. Recently, the mammalian sirtuins have been connected to an ever widening circle of activities that encompass cellular stress resistance, genomic stability, tumorigenesis and energy metabolism. Here we review the recent progress in sirtuin biology, the role these proteins have in various age-related diseases and the tantalizing notion that the activity of this family of enzymes somehow regulates how long we live.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3727385/" 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/PMC3727385/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Finkel, Toren -- Deng, Chu-Xia -- Mostoslavsky, Raul -- R01 DK088190/DK/NIDDK NIH HHS/ -- R01 GM093072/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2009 Jul 30;460(7255):587-91. doi: 10.1038/nature08197.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Translational Medicine Branch, National Heart Lung and Blood Institute, US 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/19641587" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/physiology ; Animals ; DNA Repair/physiology ; Gene Expression Regulation, Enzymologic ; Humans ; Longevity/physiology ; Sirtuins/metabolism/*physiology ; Stress, Physiological/physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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