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Protein kinase A-regulated assembly of a MEF2{middle dot}HDAC4 repressor complex controls c-Jun expression in vascular smooth muscle cells.

Authors: Gordon, JW  Pagiatakis, C  Salma, J  Du, M  Andreucci, JJ  Zhao, J  Hou, G  Perry, RL  Dan, Q  Courtman, D  Bendeck, MP  McDermott, JC 
Citation: Gordon JW, etal., J Biol Chem. 2009 Jul 10;284(28):19027-42. doi: 10.1074/jbc.M109.000539. Epub 2009 Apr 23.
Pubmed: (View Article at PubMed) PMID:19389706
DOI: Full-text: DOI:10.1074/jbc.M109.000539

Vascular smooth muscle cells (VSMCs) maintain the ability to modulate their phenotype in response to changing environmental stimuli. This phenotype modulation plays a critical role in the development of most vascular disease states. In these studies, stimulation of cultured vascular smooth muscle cells with platelet-derived growth factor resulted in marked induction of c-jun expression, which was attenuated by protein kinase Cdelta and calcium/calmodulin-dependent protein kinase inhibition. Given that these signaling pathways have been shown to relieve the repressive effects of class II histone deacetylases (HDACs) on myocyte enhancer factor (MEF) 2 proteins, we ectopically expressed HDAC4 and observed repression of c-jun expression. Congruently, suppression of HDAC4 by RNA interference resulted in enhanced c-jun expression. Consistent with these findings, mutation of the MEF2 cis-element in the c-jun promoter resulted in promoter activation during quiescent conditions, suggesting that the MEF2 cis-element functions as a repressor in this context. Furthermore, we demonstrate that protein kinase A attenuates c-Jun expression by promoting the formation of a MEF2.HDAC4 repressor complex by inhibiting salt-inducible kinase 1. Finally, we document a physical interaction between c-Jun and myocardin, and we document that forced expression of c-Jun represses the ability of myocardin to activate smooth muscle gene expression. Thus, MEF2 and HDAC4 act to repress c-Jun expression in quiescent VSMCs, protein kinase A enhances this repression, and platelet-derived growth factor derepresses c-Jun expression through calcium/calmodulin-dependent protein kinases and novel protein kinase Cs. Regulation of this molecular "switch" on the c-jun promoter may thus prove critical for toggling between the activated and quiescent VSMC phenotypes.


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CRRD Object Information
CRRD ID: 9681448
Created: 2014-12-01
Species: All species
Last Modified: 2014-12-01
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.