Silent Information Regulator 2 Potentiates Foxo1-Mediated Transcription through Its Deacetylase Activity

Longevity regulatory genes include the Forkhead transcription factor FOXO and the NAD-dependent histone deacetylase silent information regulator 2 (Sir2). Genetic studies demonstrate that Sir2 acts to extend lifespan in Caenorhabditis elegans upstream of DAF-16, a member of the FOXO family, in the i...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 101; no. 27; pp. 10042 - 10047
Main Authors Daitoku, Hiroaki, Hatta, Mitsutoki, Matsuzaki, Hitomi, Aratani, Satoko, Ohshima, Takayuki, Miyagishi, Makoto, Nakajima, Toshihiro, Fukamizu, Akiyoshi, Kenyon, Cynthia J.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 06.07.2004
National Acad Sciences
Subjects
Acetylation
Animals
Antibodies
Biochemistry
Biological Sciences
Caloric Restriction
Cell extracts
CREB-Binding Protein
Forkhead Box Protein O1
Forkhead Transcription Factors
Gene expression
Gene Expression Regulation
Genes
HEK293 cells
Hep G2 cells
Histones
Humans
Insulin
Longevity
Mice
Nuclear Proteins - metabolism
Proteins
Sirtuins - physiology
Trans-Activators - metabolism
Transcription Factors - physiology
Transcription, Genetic
Transcriptional regulatory elements
Up-Regulation
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Summary:Longevity regulatory genes include the Forkhead transcription factor FOXO and the NAD-dependent histone deacetylase silent information regulator 2 (Sir2). Genetic studies demonstrate that Sir2 acts to extend lifespan in Caenorhabditis elegans upstream of DAF-16, a member of the FOXO family, in the insulin-like signaling pathway. However, the molecular mechanisms underlying the requirement of DAF-16 activity in Sir2-mediated longevity remain unknown. Here we show that reversible acetylation of Foxo1 (also known as FKHR), the mouse DAF-16 ortholog, modulates its transactivation function. cAMP-response element-binding protein (CREB)-binding protein binds and acetylates Foxo1 at the K242, K245, and K262 residues, the modification of which is involved in the attenuation of Foxo1 as a transcription factor. Conversely, Sir2 binds and deacetylates Foxo1 at residues acetylated by cAMP-response element-binding protein-binding protein. Sir2 is recruited to insulin response sequence-containing promoter and increases the expression of manganese superoxide dismutase and p27 kip1 in a deacetylase-activity-dependent manner. Our findings establish Foxo1 as a direct and functional target for Sir2 in mammalian systems.
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This paper was submitted directly (Track II) to the PNAS office.
To whom correspondence should be addressed. E-mail: akif@tara.tsukuba.ac.jp.
Edited by Cynthia J. Kenyon, University of California, San Francisco, CA
Abbreviations: Sir, silent information regulator; CR, calorie restriction; CBP, cAMP-response element-binding protein-binding protein; HA, hemagglutinin; MnSOD, manganese superoxide dismutase; HAT, histone acetyltransferase; NIA, nicotinamide.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0400593101