The coactivator p300 directly acetylates the forkhead transcription factor Foxo1 and stimulates Foxo1-induced transcription.
The FOXO (Forkhead box class O) subgroup of forkhead transcription factors controls the expression of many genes involved in fundamental cellular processes. Until recently, studies conducted on posttranslational modifications of Forkhead proteins were restricted to their phosphorylation. In this report, we show that the coactivator p300 directly acetylates lysines in the carboxyl-terminal region of Foxo1 in vivo and in vitro, and potently stimulates Foxo1-induced transcription of IGF-binding protein-1 in transient transfection experiments. The intrinsic acetyltransferase activity of p300 is required for both activities. Our results suggest that acetylation of Foxo1 by p300 is responsible, at least in part, for its increased transactivation potency, although acetylation of histones cannot be excluded. Insulin, the major negative regulator of Foxo1-stimulated transcription, potently enhances p300 acetylation of Foxo1. Three consensus protein kinase B/Akt phosphorylation sites whose phosphorylation is stimulated by insulin are required for insulin-induced acetylation of Foxo1. In contrast to its importance in regulating the transcriptional activity of Foxo1 in the absence of insulin, acetylation plays only a minor role compared with phosphorylation in insulin inhibition of Foxo1 transcriptional activity.
Perrot
Valérie
V
Growth and Development Section, Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Building 10, Room 8D12, Bethesda, Maryland 20892, USA.
Rechler
Matthew M
MM
D000107:Acetylation; D000123:Acetyltransferases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D018970:Insulin-Like Growth Factor Binding Protein 1; D018969:Insulin-Like Growth Factor Binding Proteins / Q000235:genetics*; D010766:Phosphorylation; D011257:Pregnancy Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051381:Rats; D015533:Transcriptional Activation
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C032231:IGFBP1 protein, human; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018969:Insulin-Like Growth Factor Binding Proteins; D011257:Pregnancy Proteins; D000123:Acetyltransferases