title: Control of Foxo1 gene expression by co-activator P300.
abstract: FOXO1 is an important downstream mediator of the insulin signaling pathway. In the fed state, elevated insulin phosphorylates FOXO1 via AKT, leading to its nuclear exclusion and degradation. A reduction in nuclear FOXO1 levels then leads to suppression of hepatic glucose production. However, the mechanism leading to expression of Foxo1 gene in the fasted state is less clear. We found that Foxo1 mRNA and FOXO1 protein levels of Foxo1 were increased significantly in the liver of mice after 16 h of fasting. Furthermore, dibutyrl cAMP stimulated the expression of Foxo1 at both mRNA and protein level in hepatocytes. Because cAMP-PKA regulates hepatic glucose production through cAMP-response element-binding protein co-activators, we depleted these co-activators using adenoviral shRNAs. Interestingly, only depletion of co-activator P300 resulted in the decrease of Foxo1 mRNA and FOXO1 protein levels. In addition, inhibition of histone acetyltransferase activity of P300 significantly decreased hepatic Foxo1 mRNA and FOXO1 protein levels in fasted mice, as well as fasting blood glucose levels. By characterization of Foxo1 gene promoter, P300 regulates the Foxo1 gene expression through the binding to tandem cAMP-response element sites in the proximal promoter region of Foxo1 gene.
authors.affiliation: From the Division of Metabolism, Department of Pediatrics and.
authors.forename: Anne R
authors.initials: AR
authors.lastname: Wondisford
authors.forename: Lishou
authors.initials: L
authors.lastname: Xiong
authors.forename: Evan
authors.initials: E
authors.lastname: Chang
authors.forename: Shumei
authors.initials: S
authors.lastname: Meng
authors.forename: David J
authors.initials: DJ
authors.lastname: Meyers
authors.forename: Mingsong
authors.initials: M
authors.lastname: Li
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
authors.forename: Ling
authors.initials: L
authors.lastname: He
mesh_terms: D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005215:Fasting / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D003994:Bucladesine
keywords: CREB; Foxo; Gluconeogenesis; Histone Acetylase; P300