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 ␣ (ER␣) mediates the protective effects of estrogen in injured blood vessels and regulates ligand-dependent gene expression in vascular cells. However, the molecular mechanisms mediating ER␣-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 myocardinmediated transcriptional activation of VSMC-specific, CArGcontaining 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. steroid hormone receptors ͉ transcriptional coregulators ͉ vascular biology I n addition to an important role in growth and development of reproductive tissues, estrogen and its receptors regulate a variety of cardiovascular functions, including vascular tone and the response of blood vessels to injury (1, 2). The pleiotropic effects of estrogen are mediated through binding to its two cognate receptors, estrogen receptors ␣ (ER␣) and ␤ (ER␤), members of the nuclear hormone receptor (NHR) superfamily. NHRs are ligand-dependent transcription factors, regulating target gene expression by recruiting coactivator or corepressor complexes to their target promoters (3). Steroid receptor coactivator (SRC) 3 (SRC3) (RAC3/AIB1/TRAM1/pCIP) is a member of the p160 family of NHR coactivators including SRC1 and TIF2 (thyroid hormone receptor interacting factor 2 or SRC2) (4, 5). These molecules were initially identified as liganddependent nuclear receptor coactivators that interact with ligand-bound nuclear receptors to modulate target gene activation (3, 6-9). The SRC proteins recruit protein acetyltransferases such as cAMP response element-binding protein binding protein (CBP)/p300 and p/CAF (10-12) and protein methytransferases such as coactivator-associated arginine methyltransferase 1 (CARM-1) and protein arginine methyltransferase-1 (PRMT-1) to nuclear receptor target gene promoters to modify chromatin structure and/or assemble transcription initiation (13,14). Biochemical studies support that SRC complexes are essential for nuclear receptor activities. The SRC family of coactivators share a signature motif of LXXLL sequence...

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