title: Protein kinase A-regulated assembly of a MEF2{middle dot}HDAC4 repressor complex controls c-Jun expression in vascular smooth muscle cells.
abstract: 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.
authors.affiliation: Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Gordon
authors.forename: Christina
authors.initials: C
authors.lastname: Pagiatakis
authors.forename: Jahan
authors.initials: J
authors.lastname: Salma
authors.forename: Min
authors.initials: M
authors.lastname: Du
authors.forename: John J
authors.initials: JJ
authors.lastname: Andreucci
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Zhao
authors.forename: Guangpei
authors.initials: G
authors.lastname: Hou
authors.forename: Robert L
authors.initials: RL
authors.lastname: Perry
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Dan
authors.forename: David
authors.initials: D
authors.lastname: Courtman
authors.forename: Michelle P
authors.initials: MP
authors.lastname: Bendeck
authors.forename: John C
authors.initials: JC
authors.lastname: McDermott
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism; D000099251:Myocardin
chemical_list: D017868:Cyclic AMP-Dependent Protein Kinases; D006655:Histone Deacetylases; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000099251:Myocardin; C578036:Mef2a protein, mouse; C498618:Hdac5 protein, mouse