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

Jun-Xing Zhao1, Wan-Fu Yue, Mei-Jun Zhu

  • 1Department of Animal Science, University of Wyoming, Laramie, Wyoming 82071, USA.

The Journal of Biological Chemistry
|April 2, 2011
PubMed

Insights

AMP-activated protein kinase (AMPK) promotes cell differentiation by regulating β-catenin expression. It achieves this by phosphorylating histone deacetylase 5 (HDAC5), impacting the Wnt/β-catenin pathway.

Area of Science:

  • Cell Biology
  • Metabolism
  • Epigenetics

Background:

  • AMP-activated protein kinase (AMPK) is crucial for energy metabolism and is implicated in cell differentiation.
  • The precise mechanisms by which AMPK influences cell differentiation remain largely unknown.
  • The Wnt/β-catenin signaling pathway plays a vital role in cell differentiation and development.

Purpose of the Study:

  • To investigate the role of AMPK in regulating cell differentiation.
  • To elucidate the molecular mechanisms linking AMPK to β-catenin expression.
  • To explore the involvement of histone deacetylase 5 (HDAC5) in AMPK-mediated regulation of β-catenin.

Main Methods:

  • Utilized C3H10T1/2 cells and mouse embryonic fibroblasts (MEFs).
  • Assessed AMPK activity, β-catenin levels, and H3K9 acetylation.
  • Employed chemical inhibition and overexpression/knockdown of HDAC5.
  • Investigated protein-protein interactions between HDAC5 and myocyte enhancer factor-2 (MEF2).
  • Performed site-directed mutagenesis on HDAC5 phosphorylation sites.

Main Results:

  • AMPK activity positively correlated with β-catenin content in cells.
  • HDAC5 inhibition increased β-catenin mRNA expression.
  • AMPK phosphorylated HDAC5, leading to its nuclear export.
  • Mutations in HDAC5 phosphorylation sites abolished AMPK's regulatory effect on β-catenin.
  • HDAC5 forms a complex with MEF2 to down-regulate β-catenin.

Conclusions:

  • AMPK promotes β-catenin expression via phosphorylation of HDAC5.
  • Phosphorylation of HDAC5 by AMPK reduces its interaction with the β-catenin promoter through MEF2.
  • AMPK regulates cell differentiation and development through cross-talk with the Wnt/β-catenin signaling pathway.

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