title: Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4.
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.
authors: Department of Cardiology, University of Heidelberg, 69120 Heidelberg, Germany. johannes.backs@med.uni-heidelberg.de
authors: Johannes
authors: J
authors: Backs
authors: Barbara C
authors: BC
authors: Worst
authors: Lorenz H
authors: LH
authors: Lehmann
authors: David M
authors: DM
authors: Patrick
authors: Zegeye
authors: Z
authors: Jebessa
authors: Michael M
authors: MM
authors: Kreusser
authors: Qiang
authors: Q
authors: Sun
authors: Lan
authors: L
authors: Chen
authors: Claudia
authors: C
authors: Heft
authors: Hugo A
authors: HA
authors: Katus
authors: Eric N
authors: EN
authors: Olson
mesh_terms: D000818:Animals; D019556:COS Cells; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D059748:Proteolysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction
chemical_list: D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D017868:Cyclic AMP-Dependent Protein Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D006655:Histone Deacetylases