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AMP‐activated protein kinase regulates β‐catenin transcription via histone deacetylase 5
Author(s) -
Zhao JunXing,
Yue WanFu,
Zhu MeiJun,
Du Min
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1105.18
Subject(s) - histone deacetylase 5 , ampk , histone deacetylase , microbiology and biotechnology , wnt signaling pathway , mef2 , phosphorylation , catenin , protein kinase a , transcription factor , biology , chemistry , signal transduction , histone , biochemistry , enhancer , gene
AMP‐activated protein kinase (AMPK) is a key regulator of energy metabolism; it is inhibited under obese conditions and is activated by exercise and many anti‐diabetic drugs. Emerging evidence also suggests that AMPK regulates cell differentiation including inhibition of adipogenesis and enhancing myogenesis, but the underlying mechanisms are unclear. β‐Catenin not only regulates cell to cell adhesion, but also acts as a key component of Wnt/β‐catenin signaling pathway, a pathway known to promote myogenesis and inhibit adipogenesis. 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 over‐expression reduced and HDAC5 knockdown increased H3K9 acetylation and cellular β‐catenin content. Over‐expression of HDAC5 reduced β‐catenin promoter transcriptional activity, which was further abolished by mutation of myocyte enhancer factor‐2 (MEF2) binding site. AMPK phosphorylated HDAC5, which promoted HDAC5 interaction with 14‐3‐3 and exported 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 MEF2. Thus, the data indicate that AMPK regulates cell differentiation and development via crosstalk with the wingless and Int (Wnt)/β‐catenin signaling pathway.