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 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.
Mesh Terms:
Acetylation, Animals, CREB-Binding Protein, Caloric Restriction, Forkhead Transcription Factors, Gene Expression Regulation, Humans, Longevity, Mice, Nuclear Proteins, Sirtuins, Trans-Activators, Transcription Factors, Transcription, Genetic, Up-Regulation
Proc. Natl. Acad. Sci. U.S.A.
Date: Jul. 06, 2004
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