Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase

Anne Brunet; Lora B Sweeney; J Fitzhugh Sturgill; Katrin F Chua; Paul L Greer; Yingxi Lin; Hien Tran; Sarah E Ross; Raul Mostoslavsky; Haim Y Cohen; Linda S Hu; Hwei-Ling Cheng; Mark P Jedrychowski; Steven P Gygi; David A Sinclair; Frederick W Alt; Michael E Greenberg

doi:10.1126/science.1094637

Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase

Science. 2004 Mar 26;303(5666):2011-5. doi: 10.1126/science.1094637. Epub 2004 Feb 19.

Authors

Anne Brunet¹, Lora B Sweeney, J Fitzhugh Sturgill, Katrin F Chua, Paul L Greer, Yingxi Lin, Hien Tran, Sarah E Ross, Raul Mostoslavsky, Haim Y Cohen, Linda S Hu, Hwei-Ling Cheng, Mark P Jedrychowski, Steven P Gygi, David A Sinclair, Frederick W Alt, Michael E Greenberg

Affiliation

¹ 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.

PMID: 14976264
DOI: 10.1126/science.1094637

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Acetylation
Animals
Apoptosis
Cell Cycle
Cell Line
Cell Nucleus / metabolism
Cells, Cultured
Cerebellum / cytology
Forkhead Box Protein O3
Forkhead Transcription Factors
GADD45 Proteins
Gene Expression Profiling
Gene Expression Regulation
Histone Deacetylases / genetics
Histone Deacetylases / metabolism*
Humans
Intracellular Signaling Peptides and Proteins
Mice
Mice, Knockout
Neurons / cytology
Oxidative Stress*
Phosphorylation
Proteins / genetics
Recombinant Proteins / metabolism
Sirtuin 1
Sirtuins / genetics
Sirtuins / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism*
Transcription, Genetic

Substances

Forkhead Box Protein O3
Forkhead Transcription Factors
FoxO3 protein, mouse
Intracellular Signaling Peptides and Proteins
Proteins
Recombinant Proteins
Transcription Factors
SIRT1 protein, human
Sirt1 protein, mouse
Sirtuin 1
Sirtuins
Histone Deacetylases

Abstract

Publication types

MeSH terms

Substances

Grants and funding