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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1301509110

Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy.

Publication TypeJournal Article
Year of Publication2013
AuthorsFerguson, BS, Harrison, BC, Jeong, MY, Reid, BG, Wempe, MF, Wagner, FF, Holson, EB, McKinsey, TA
JournalProc Natl Acad Sci U S A
Volume110
Issue24
Pages9806-11
Date Published2013 Jun 11
ISSN1091-6490
KeywordsAnimals, Animals, Newborn, Benzamides, Cardiomegaly, Cell Nucleus, Cells, Cultured, Dual-Specificity Phosphatases, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Histone Deacetylase Inhibitors, Histone Deacetylases, Immunoblotting, Male, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Myocytes, Cardiac, Pyrimidines, Rats, Rats, Sprague-Dawley, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Signal Transduction
Abstract

Cardiac hypertrophy is a strong predictor of morbidity and mortality in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors have been shown to suppress cardiac hypertrophy through mechanisms that remain poorly understood. We report that class I HDACs function as signal-dependent repressors of cardiac hypertrophy via inhibition of the gene encoding dual-specificity phosphatase 5 (DUSP5) DUSP5, a nuclear phosphatase that negatively regulates prohypertrophic signaling by ERK1/2. Inhibition of DUSP5 by class I HDACs requires activity of the ERK kinase, mitogen-activated protein kinase kinase (MEK), revealing a self-reinforcing mechanism for promotion of cardiac ERK signaling. In cardiac myocytes treated with highly selective class I HDAC inhibitors, nuclear ERK1/2 signaling is suppressed in a manner that is absolutely dependent on DUSP5. In contrast, cytosolic ERK1/2 activation is maintained under these same conditions. Ectopic expression of DUSP5 in cardiomyocytes results in potent inhibition of agonist-dependent hypertrophy through a mechanism involving suppression of the gene program for hypertrophic growth. These findings define unique roles for class I HDACs and DUSP5 as integral components of a regulatory signaling circuit that controls cardiac hypertrophy.

DOI10.1073/pnas.1301509110
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23720316?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID23720316
PubMed Central IDPMC3683796
Grant ListK01 AR055676 / AR / NIAMS NIH HHS / United States
T32 HL007822 / HL / NHLBI NIH HHS / United States
UL1 TR001082 / TR / NCATS NIH HHS / United States
5T32HL007822-12 / HL / NHLBI NIH HHS / United States