title: 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 β-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 β-catenin content. Chemical inhibition of HDAC5 increased β-catenin mRNA expression. HDAC5 overexpression reduced and HDAC5 knockdown increased H3K9 acetylation and cellular β-catenin content. HDAC5 formed a complex with myocyte enhancer factor-2 to down-regulate β-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 β-catenin expression. In conclusion, AMPK promotes β-catenin expression through phosphorylation of HDAC5, which reduces HDAC5 interaction with the β-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)/β-catenin signaling pathway.
authors: Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071, USA.
authors: Jun-Xing
authors: JX
authors: Zhao
authors: Wan-Fu
authors: WF
authors: Yue
authors: Mei-Jun
authors: MJ
authors: Zhu
authors: Min
authors: M
authors: Du
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000107:Acetylation; D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018006:Myogenic Regulatory Factors / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011494:Protein Kinases; D015398:Signal Transduction / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D018006:Myogenic Regulatory Factors; D051153:Wnt Proteins; D051176:beta Catenin; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases