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  • 1
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    Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase (2004)
    American Association for the Advancement of Science (AAAS)
    Details
    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
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    The sirtuin SIRT6 regulates lifespan in male mice (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-03-01
    Description: The significant increase in human lifespan during the past century confronts us with great medical challenges. To meet these challenges, the mechanisms that determine healthy ageing must be understood and controlled. Sirtuins are highly conserved deacetylases that have been shown to regulate lifespan in yeast, nematodes and fruitflies. However, the role of sirtuins in regulating worm and fly lifespan has recently become controversial. Moreover, the role of the seven mammalian sirtuins, SIRT1 to SIRT7 (homologues of the yeast sirtuin Sir2), in regulating lifespan is unclear. Here we show that male, but not female, transgenic mice overexpressing Sirt6 (ref. 4) have a significantly longer lifespan than wild-type mice. Gene expression analysis revealed significant differences between male Sirt6-transgenic mice and male wild-type mice: transgenic males displayed lower serum levels of insulin-like growth factor 1 (IGF1), higher levels of IGF-binding protein 1 and altered phosphorylation levels of major components of IGF1 signalling, a key pathway in the regulation of lifespan. This study shows the regulation of mammalian lifespan by a sirtuin family member and has important therapeutic implications for age-related diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kanfi, Yariv -- Naiman, Shoshana -- Amir, Gail -- Peshti, Victoria -- Zinman, Guy -- Nahum, Liat -- Bar-Joseph, Ziv -- Cohen, Haim Y -- 1R01GM085022/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Feb 22;483(7388):218-21. doi: 10.1038/nature10815.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22367546" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Female ; Gene Expression ; Gene Expression Profiling ; Insulin-Like Growth Factor I/analysis ; Kaplan-Meier Estimate ; Longevity/genetics/*physiology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Transgenic ; Oligonucleotide Array Sequence Analysis ; *Sex Characteristics ; Sirtuins/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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