AMP-activated protein kinase regulates beta-catenin transcription via histone deacetylase 5.

ABSTRACT: AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism; it is inhibited under obese conditions and is activated by exercise and by many anti-diabetic drugs. Emerging evidence also suggests that AMPK regulates cell differentiation, but the underlying mechanisms are unclear. We hypothesized that AMPK regulates cell differentiation via altering ?-catenin expression, which involves phosphorylation of class IIa histone deacetylase 5 (HDAC5). In both C3H10T1/2 cells and mouse embryonic fibroblasts (MEFs), AMPK activity was positively correlated with ?-catenin content. Chemical inhibition of HDAC5 increased ?-catenin mRNA expression. HDAC5 overexpression reduced and HDAC5 knockdown increased H3K9 acetylation and cellular ?-catenin content. HDAC5 formed a complex with myocyte enhancer factor-2 to down-regulate ?-catenin mRNA expression. AMPK phosphorylated HDAC5, which promoted HDAC5 exportation from the nucleus; mutation of two phosphorylation sites in HDAC5, Ser-259 and -498, abolished the regulatory role of AMPK on ?-catenin expression. In conclusion, AMPK promotes ?-catenin expression through phosphorylation of HDAC5, which reduces HDAC5 interaction with the ?-catenin promoter via myocyte enhancer factor-2. Thus, the data indicate that AMPK regulates cell differentiation and development via cross-talk with the wingless and Int (Wnt)/?-catenin signaling pathway.

SUBMITTER: Zhao JX 

PROVIDER: S-EPMC3091248 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature