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C. elegans SIRT6/7 Homolog SIR-2.4 Promotes DAF-16 Relocalization and Function during Stress
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نویسنده
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chiang w.-c. ,tishkoff d.x. ,yang b. ,wilson-grady j. ,yu x. ,mazer t. ,eckersdorff m. ,gygi s.p. ,lombard d.b. ,hsu a.-l.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 9
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چکیده
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Foxo transcription factors and sirtuin family deacetylases regulate diverse biological processes,including stress responses and longevity. here we show that the caenorhabditis elegans sirtuin sir-2.4-homolog of mammalian sirt6 and sirt7 proteins-promotes daf-16-dependent transcription and stress-induced daf-16 nuclear localization. sir-2.4 is required for resistance to multiple stressors: heat shock,oxidative insult,and proteotoxicity. by contrast,sir-2.4 is largely dispensable for daf-16 nuclear localization and function in response to reduced insulin/igf-1-like signaling. although acetylation is known to regulate localization and activity of mammalian foxo proteins,this modification has not been previously described on daf-16. we find that daf-16 is hyperacetylated in sir-2.4 mutants. conversely,daf-16 is acetylated by the acetyltransferase cbp-1,and daf-16 is hypoacetylated and constitutively nuclear in response to cbp-1 inhibition. surprisingly,a sir-2.4 catalytic mutant efficiently rescues the daf-16 localization defect in sir-2.4 null animals. acetylation of daf-16 by cbp-1 in vitro is inhibited by either wild-type or mutant sir-2.4,suggesting that sir-2.4 regulates daf-16 acetylation indirectly,by preventing cbp-1-mediated acetylation under stress conditions. taken together,our results identify sir-2.4 as a critical regulator of daf-16 specifically in the context of stress responses. furthermore,they reveal a novel role for acetylation,modulated by the antagonistic activities of cbp-1 and sir-2.4,in modulating daf-16 localization and function. © 2012 chiang et al.
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آدرس
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department of molecular and integrative physiology,university of michigan,ann arbor,mi, United States, department of pathology,university of michigan,ann arbor,mi, United States, department of pathology,university of michigan,ann arbor,mi, United States, department of cell biology,harvard medical school,boston,ma, United States, department of internal medicine,division of geriatric medicine,university of michigan,ann arbor,mi, United States, department of internal medicine,division of geriatric medicine,university of michigan,ann arbor,mi, United States, department of pathology,university of michigan,ann arbor,mi,united states,regeneron pharmaceuticals,tarrytown,ny, United States, department of cell biology,harvard medical school,boston,ma, United States, department of pathology,university of michigan,ann arbor,mi,united states,institute of gerontology and the geriatrics center,university of michigan,ann arbor,mi, United States, department of molecular and integrative physiology,university of michigan,ann arbor,mi,united states,department of internal medicine,division of geriatric medicine,university of michigan,ann arbor,mi,united states,institute of gerontology and the geriatrics center,university of michigan,ann arbor,mi, United States
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Authors
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