SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1

被引:268
作者
Bouras, T
Fu, MF
Sauve, AA
Wang, F
Quong, AA
Perkins, ND
Hay, RT
Gu, W
Pestell, RG
机构
[1] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA
[2] Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA
[3] Albert Einstein Coll Med, Lab Macromol Anal & Proteom, Bronx, NY 10461 USA
[4] Univ Dundee, Sch Life Sci, Div Gene Regulat & Express, Dundee DD15 5EH, Scotland
[5] Univ St Andrews, Ctr Biomol Sci, St Andrews KY16 9TS, Fife, Scotland
[6] Columbia Univ Coll Phys & Surg, Inst Transgenet, New York, NY 10032 USA
[7] Columbia Univ Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA
关键词
D O I
10.1074/jbc.M408748200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The SIR2 family of nicotinamide adenosine dinucleotide (NAD)-dependent deacetylases modulates diverse biological functions in different species, including longevity, apoptosis, cell cycle exit, and cellular differentiation. SIRT1, the closest mammalian ortholog of the yeast SIR2 ( silent information regulator 2) gene, represses several transcription factors, including p53, NF kappa B and forkhead proteins. The p300 protein serves as a rate-limiting transcriptional cointegrator of diverse transcription factors either to activate or to repress transcription through modular subdomains. Herein, SIRT1 physically interacted with and repressed p300 transactivation, requiring the NAD-dependent deacetylase activity of SIRT1. SIRT1 repression involved the CRD1 transcriptional repression domain of p300. Two residues within the CRD1 domain (Lys-1020 and Lys-1024) were required for SIRT1 repression and served as substrates for SIRT1 deacetylation. These residues also serve as acceptor lysines for modification by the ubiquitin-like SUMO protein. The SUMO-specific protease SSP3 relieved SIRT1 repression of p300. SSP3 antagonism of SIRT1 required the SUMO-deconjugating function of SSP3. Thus, p300 serves as a deacetylase substrate for SIRT1 through a conserved SUMO consensus motif. Because p300 is a limiting transcriptional cofactor, deacetylation and repression of p300 by SIRT1 may serve an important integration point during metabolism and cellular differentiation.
引用
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页码:10264 / 10276
页数:13
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