Numerous physiological and pathological stimuli promote the rearrangement of the actin cytoskeleton, thereby modulating cellular motile functions. Although it seems intuitively obvious that cell motility requires coordinated protein biosynthesis, until recently the linkage between cytoskeletal actin dynamics and correlated gene activities remained unknown. This knowledge gap was filled in part by the discovery that globular actin polymerization liberates myocardin-related transcription factor (MRTF) cofactors, thereby inducing the nuclear transcription factor serum response factor (SRF) to modulate the expression of genes encoding structural and regulatory effectors of actin dynamics. This insight stimulated research to better understand the actin–MRTF–SRF circuit and to identify alternative mechanisms that link cytoskeletal dynamics and genome activity.

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Smooth muscle cells switch between differentiated and proliferative phenotypes in response to extracellular cues, but the transcriptional mechanisms that confer such phenotypic plasticity remain unclear. Serum response factor (SRF) activates genes involved in smooth muscle differentiation and proliferation by recruiting muscle-restricted cofactors, such as the transcriptional coactivator myocardin, and ternary complex factors (TCFs) of the ETS-domain family, respectively. Here we show that growth signals repress smooth muscle genes by triggering the displacement of myocardin from SRF by Elk-1, a TCF that acts as a myogenic repressor. The opposing influences of myocardin and Elk-1 on smooth muscle gene expression are mediated by structurally related SRF-binding motifs that compete for a common docking site on SRF. A mutant smooth muscle promoter, retaining responsiveness to myocardin and SRF but defective in TCF binding, directs ectopic transcription in the embryonic heart, demonstrating a role for TCFs in suppression of smooth muscle gene expression in vivo. We conclude that growth and developmental signals modulate smooth muscle gene expression by regulating the association of SRF with antagonistic cofactors.

Myocardin is a SAP (SAF-A͞B, Acinus, PIAS) domain transcription factor that associates with serum response factor (SRF) to potently enhance SRF-dependent transcription. Here we describe two myocardin-related transcription factors (MRTFs), A and B, that also interact with SRF and stimulate its transcriptional activity. Whereas myocardin is expressed specifically in cardiac and smooth muscle cells, MRTF-A and -B are expressed in numerous embryonic and adult tissues. In SRF-deficient embryonic stem cells, myocardin and MRTFs are unable to activate SRF-dependent reporter genes, confirming their dependence on SRF. Myocardin and MRTFs comprise a previously uncharacterized family of SRF cofactors with the potential to modulate SRF target genes in a wide range of tissues.

Ternary complex factors (TCFs), one of which is Elk‐1, have been implicated in mediation of c‐fos induction. They have been shown to be phosphorylated by mitogen‐activated protein kinases (MAPKs) in vitro. We demonstrate that recombinant Elk‐1 is hyperphosphorylated in vivo upon joint overexpression of MAPKs and constitutively activated Raf‐1 kinase, the latter serving as an indirect in vivo activator of MAPKs. This phosphorylation is accompanied by a conformational change and results in an elevated transactivation potential of Elk‐1. Mutation of mapped in vivo phosphorylation sites, which are potential targets for MAPKs, reduced Elk‐1‐mediated transcription. Thus, MAPKs are very probably controlling Elk‐1 activity by direct phosphorylation in vivo. Furthermore, Elk‐1 was shown to stimulate transcription from both the c‐fos serum response element and also from an Ets binding site. While binding of TCFs to the c‐fos promoter is dependent on the serum response factor, TCFs can autonomously interact with Ets binding sites. This indicates that TCFs may participate in the transcriptional regulation of two different sets of genes.