Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity

摘要: Longevity regulatory genes include the Forkhead transcription factor FOXO and 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 family, insulin-like signaling pathway. However, molecular mechanisms underlying requirement DAF-16 activity Sir2-mediated longevity remain unknown. Here we show reversible acetylation Foxo1 (also known as FKHR), mouse ortholog, modulates its transactivation function. cAMP-response element-binding protein (CREB)-binding binds acetylates at K242, K245, K262 residues, modification which is involved attenuation factor. Conversely, deacetylates residues acetylated by protein-binding protein. recruited insulin response sequence-containing promoter increases expression manganese superoxide dismutase p27kip1 deacetylase-activity-dependent manner. Our findings establish direct functional target for mammalian systems.