title: Steroid receptor coactivator 3 is a coactivator for myocardin, the regulator of smooth muscle transcription and differentiation.
abstract: Abnormal proliferation of vascular smooth muscle cells (VSMCs) constitutes a key event in atherosclerosis, neointimal hyperplasia, and the response to vascular injury. Estrogen receptor alpha (ERalpha) mediates the protective effects of estrogen in injured blood vessels and regulates ligand-dependent gene expression in vascular cells. However, the molecular mechanisms mediating ERalpha-dependent VSMC gene expression and VSMC proliferation after vascular injury are not well defined. Here, we report that the ER coactivator steroid receptor coactivator 3 (SRC3) is also a coactivator for the major VSMC transcription factor myocardin, which is required for VSMC differentiation to the nonproliferative, contractile state. The N terminus of SRC3, which contains a basic helix-loop-helix/Per-ARNT-Sim protein-protein interaction domain, binds the C-terminal activation domain of myocardin and enhances myocardin-mediated transcriptional activation of VSMC-specific, CArG-containing promoters, including the VSMC-specific genes SM22 and myosin heavy chain. Suppression of endogenous SRC3 expression by specific small interfering RNA attenuates myocardin transcriptional activation in cultured cells. The SRC3-myocardin interaction identifies a site of convergence for nuclear hormone receptor-mediated and VSMC-specific gene regulation and suggests a possible mechanism for the vascular protective effects of estrogen on vascular injury.
authors.affiliation: Molecular Cardiology Research Institute, Department of Medicine, and Division of Cardiology, New England Medical Center Hospitals, Tufts University School of Medicine, Boston, MA 02111, USA.
authors.forename: Hui Joyce
authors.initials: HJ
authors.lastname: Li
authors.forename: Zaffar
authors.initials: Z
authors.lastname: Haque
authors.forename: Qing
authors.initials: Q
authors.lastname: Lu
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Richard
authors.initials: R
authors.lastname: Karas
authors.forename: Michael
authors.initials: M
authors.lastname: Mendelsohn
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism; D005786:Gene Expression Regulation; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D056921:Nuclear Receptor Coactivator 3; D011485:Protein Binding; D014018:Tissue Distribution; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D014158:Transcription, Genetic; D000099251:Myocardin
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; D051548:Histone Acetyltransferases; D008024:Ligands; D009687:Nuclear Proteins; D056921:Nuclear Receptor Coactivator 3; D015534:Trans-Activators; D000099251:Myocardin; C538866:NCOA3 protein, human