1. Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4.
- Author
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Backs J, Worst BC, Lehmann LH, Patrick DM, Jebessa Z, Kreusser MM, Sun Q, Chen L, Heft C, Katus HA, and Olson EN
- Subjects
- Animals, COS Cells, Calcium-Calmodulin-Dependent Protein Kinase Type 2 genetics, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Cell Nucleus metabolism, Chlorocebus aethiops, Fluorescent Antibody Technique, Gene Expression Regulation, MEF2 Transcription Factors, Mice, Myocytes, Cardiac metabolism, Myogenic Regulatory Factors metabolism, Proteolysis, Rats, Rats, Sprague-Dawley, Signal Transduction, Cyclic AMP-Dependent Protein Kinases metabolism, Histone Deacetylases metabolism, Myogenic Regulatory Factors antagonists & inhibitors
- Abstract
Histone deacetylase 4 (HDAC4) regulates numerous gene expression programs through its signal-dependent repression of myocyte enhancer factor 2 (MEF2) and serum response factor (SRF) transcription factors. In cardiomyocytes, calcium/calmodulin-dependent protein kinase II (CaMKII) signaling promotes hypertrophy and pathological remodeling, at least in part by phosphorylating HDAC4, with consequent stimulation of MEF2 activity. In this paper, we describe a novel mechanism whereby protein kinase A (PKA) overcomes CaMKII-mediated activation of MEF2 by regulated proteolysis of HDAC4. PKA induces the generation of an N-terminal HDAC4 cleavage product (HDAC4-NT). HDAC4-NT selectively inhibits activity of MEF2 but not SRF, thereby antagonizing the prohypertrophic actions of CaMKII signaling without affecting cardiomyocyte survival. Thus, HDAC4 functions as a molecular nexus for the antagonistic actions of the CaMKII and PKA pathways. These findings have implications for understanding the molecular basis of cardioprotection and other cellular processes in which CaMKII and PKA exert opposing effects.
- Published
- 2011
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