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PMID: 12202037 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Class II histone deacetylases act as signal-responsive repressors of cardiac hypertrophy.

Cell ·Vol. 110 ·No. 4 ·2002-08-23 ·Pages 479-88

Zhang CL, McKinsey TA, Chang S, Antos CL, Hill JA, Olson EN

Abstract

The heart responds to stress signals by hypertrophic growth, which is accompanied by activation of the MEF2 transcription factor and reprogramming of cardiac gene expression. We show here that class II histone deacetylases (HDACs), which repress MEF2 activity, are substrates for a stress-responsive kinase specific for conserved serines that regulate MEF2-HDAC interactions. Signal-resistant HDAC mutants lacking these phosphorylation sites are refractory to hypertrophic signaling and inhibit cardiomyocyte hypertrophy. Conversely, mutant mice lacking the class II HDAC, HDAC9, are sensitized to hypertrophic signals and exhibit stress-dependent cardiomegaly. Thus, class II HDACs act as signal-responsive suppressors of the transcriptional program governing cardiac hypertrophy and heart failure.

MeSH Terms
Aging/genetics,metabolism,pathology Animals Calcineurin/genetics,metabolism Calcium-Calmodulin-Dependent Protein Kinase Type 1 Calcium-Calmodulin-Dependent Protein Kinases/genetics,metabolism Cardiomegaly/enzymology,genetics,physiopathology Carrier Proteins/genetics,metabolism DNA-Binding Proteins/genetics,metabolism Enzyme Inhibitors/pharmacology Gene Expression Regulation, Developmental/physiology Heart/embryology Histone Deacetylase 2 Histone Deacetylases/deficiency,genetics,metabolism Hypertension/complications,pathology,physiopathology MEF2 Transcription Factors Male Mice Mice, Knockout Mutation/genetics Myocardium/enzymology,pathology Myogenic Regulatory Factors Phosphorylation Phosphotransferases/genetics,metabolism Repressor Proteins Signal Transduction/genetics Stress, Physiological/enzymology,genetics,physiopathology Transcription Factors/genetics,metabolism Transcriptional Activation/physiology
Chemicals
Carrier Proteins DNA-Binding Proteins Enzyme Inhibitors MEF2 Transcription Factors Myogenic Regulatory Factors Repressor Proteins Transcription Factors Phosphotransferases CAMK1 protein, human Calcium-Calmodulin-Dependent Protein Kinase Type 1 Calcium-Calmodulin-Dependent Protein Kinases Camk1 protein, mouse Pnck protein, mouse Calcineurin HDAC9 protein, human Hdac2 protein, mouse Hdac5 protein, mouse Hdac9 protein, mouse Histone Deacetylase 2 Histone Deacetylases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Zhang Chun Li
Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas 75390, USA.
McKinsey Timothy A
Chang Shurong
Antos Christopher L
Hill Joseph A
Olson Eric N
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
0092-8674
DOI
10.1016/s0092-8674(02)00861-9
Published
2002-08-23
Pages
479-88
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC4459650
Subset
IM
Grants
NHLBI NIH HHS · R01 HL053351 · United States
NHLBI NIH HHS · R37 HL053351 · United States
External Links
PubMed source DOI: 10.1016/s0092-8674(02)00861-9 PMC Full Text View journal details
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