Myocardin/MKL family of SRF coactivators: Key regulators of immediate early and muscle specific gene expression

Abstract

Myocardin, megakaryoblastic leukemia-1 (MKL1), and MKL2 belong to a newly defined family of transcriptional coactivators. All three family members bind to serum response factor (SRF) and strongly activate transcription from promoters with SRF binding sites. SRF is required for the serum induction of immediate early genes such as c-fos and for the expression of many muscle specific genes. Consistent with a role in muscle specific gene expression, myocardin is specifically expressed in cardiac and smooth muscle cells while MKL1 and 2 are broadly expressed. Myocardin has particularly been shown to be required for smooth muscle development while MKL1/2 are required for the RhoA signaling pathway for induction of immediate early genes. SRF can be activated by at least two families of coactivators, p62TCF and myocardin/MKL. These factors bind to the same region of SRF such that their binding is mutually exclusive. This provides one mechanism of regulation of SRF target genes by pathways that differentially activate the coactivators. The RhoA pathway appears to activate MKL1 by altering MKL1's binding to actin and causing MKL1's translocation from the cytoplasm to the nucleus. However, this mechanism of activation of the myocardin/MKL family has not been observed in all cell types such that other regulatory mechanism(s) likely exist. In particular, rapid serum inducible phosphorylation of MKL1 was observed. The regulation of this coactivator family is key to understanding how SRF target genes are activated during muscle cell differentiation or growth factor induced cell proliferation.

Requirement for serum response factor for skeletal muscle growth and maturation revealed by tissue-specific gene deletion in mice

“…SRF cooperates with members of the myocardin family to activate specific programs of gene expression (8)(9)(10). To determine whether MRTFs might participate in the control of skeletal muscle genes in vivo, we expressed dnMRTF-A in skeletal muscle of transgenic mice by using the MCK promoter.…”

“…Members of the myocardin family stimulate SRF activity and have been implicated in differentiation of cardiac and smooth muscle (8)(9)(10)(11)(12)(13)(14)(15)(16)(17). Similarly, a dominant negative mutant of MRTF-B͞MKL2 inhibits differ- entiation of skeletal muscle cells in vitro (41).…”

“…Like MEF2 and other MADS box transcription factors, SRF activates transcription by associating with a variety of signal-responsive and cell type-restricted cofactors (7). Myocardin, an especially powerful SRF coactivator expressed specifically in cardiac and smooth muscle cells, has been shown to be necessary and sufficient for cardiac and smooth muscle gene expression (8)(9)(10)(11)(12)(13)(14)(15)(16). The myocardin-related transcription factors (MRTFs) MRTF-A (also called MAL͞MKL1͞BASC) and MRTF-B (also called MKL2) also are expressed in skeletal, cardiac, and smooth muscle cells, as well as other cell types (17)(18)(19)(20)(21).…”

Patterns of Gene Expression Differentially Regulated by Platelet-derived Growth Factor and Hypertrophic Stimuli in Vascular Smooth Muscle Cells

“…This is mediated at least in part through translocation of coactivators of the myocardin/MKL family (reviewed in Ref. 42). Our data show that…”

Activation of MRTF-A–dependent gene expression with a small molecule promotes myofibroblast differentiation and wound healing

“…Although myocardin is specifically expressed in cardiomyocytes and SMCs and is constitutively localized to the nucleus, myocardin-related transcription factor-A (MRTF-A, MKL1, MAL, BSAC) and -B (MRTF-B, MKL2) are broadly expressed and sequestered in the cytoplasm via interactions with G-actin (8,11,12,(16)(17)(18). Situations of stress that locally alter actin dynamics and promote F-actin polymerization promote nuclear accumulation of MRTFs (18)(19)(20)(21)(22)(23)(24).…”