Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4

被引：117

作者：

Backs, Johannes ^{[1
]}

Worst, Barbara C. ^{[1
]}

Lehmann, Lorenz H. ^{[1
]}

Patrick, David M. ^{[2
]}

Jebessa, Zegeye ^{[1
]}

Kreusser, Michael M. ^{[1
]}

Sun, Qiang ^{[1
]}

Chen, Lan ^{[1
]}

Heft, Claudia ^{[1
]}

Katus, Hugo A. ^{[1
]}

Olson, Eric N. ^{[2
]}

机构：

[1] Univ Heidelberg, Dept Cardiol, D-69120 Heidelberg, Germany

[2] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA

来源：

JOURNAL OF CELL BIOLOGY | 2011年 / 195卷 / 03期

基金：

美国国家卫生研究院;

关键词：

II HISTONE DEACETYLASES; CAM KINASE-II; CONGESTIVE-HEART-FAILURE; CARDIAC-HYPERTROPHY; TRANSCRIPTION FACTOR; GENE-EXPRESSION; NUCLEAR EXPORT; BETA(1)-ADRENERGIC STIMULATION; INDEPENDENT ACTIVATION; MOUSE EMBRYOGENESIS;

D O I：

10.1083/jcb.201105063

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：403 / 415

页数：13

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