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Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression

Nature volume 428, pages 185–189 (2004)Cite this article

Abstract

Smooth muscle cells switch between differentiated and proliferative phenotypes in response to extracellular cues1, 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, respectively2,3,4,5,6,7,8,9. 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.

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Figure 1: Mutually exclusive interactions of myocardin and Elk-1 with SRF in SM cells. A7r5 cells were cultured in serum-free medium and then stimulated with or without PDGF-BB (20 ng ml-1) for 24 h (a) or 30 min (b–d) in the presence or absence of U0126 (10 µM) as indicated.
Figure 2: Competition between Elk-1 and myocardin for interaction with SRF.
Figure 3: Suppression of smooth muscle gene expression by Elk-1.
Figure 4: Ectopic expression of a lacZ reporter controlled by an SM22 promoter lacking the TCF site.

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Acknowledgements

We thank A. Sharrocks, M. Parmacek and L. Schuger for reagents, A. Tizenor for graphics, J. Page for editorial assistance, L. Sutherland for technical assistance and R. Bassel-Duby, L. Li, M. Tallquist and H. Yanagisawa for discussions. This work was supported by grants from the NIH, the McGowan Foundation, the Donald W. Reynolds Foundation, and the Robert A. Welch Foundation to E.N.O., from the Muscular Dystrophy Association (MDA) and NIH to D.-Z.W., and by the DFG to A.N.

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Authors and Affiliations

  1. Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd, Dallas, Texas, 75390-9148, USA

    Zhigao Wang, Da-Zhi Wang, John McAnally & Eric N. Olson

  2. Carolina Cardiovascular Biology Center, Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, North Carolina, 27599-7126, USA

    Da-Zhi Wang

  3. Institute of Cell Biology, Department of Molecular Biology, Tuebingen University, D-72704, Tuebingen, Germany

    Dirk Hockemeyer & Alfred Nordheim

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Correspondence to Eric N. Olson.

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The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure 1

Modulation of smooth muscle gene expression by PDGF. (JPG 42 kb)

Supplementary Figure 2

ChIP assay to detect association of myocardin and Elk-1 with the a-smooth muscle actin gene promoter. (JPG 35 kb)

Supplementary Figure 3

Gel mobility shift assays with the CArG and TCF binding sites from the c-fos and SM22 promoter. (JPG 64 kb)

Supplementary Figure 4

Loss of myogenic activity of myocardin mutant L291P. (JPG 26 kb)

Supplementary Figure 5

Phosphorylation of Elk-1 in the presence of serum and inhibition by U0126. (JPG 28 kb)

Supplementary Figure 6

Repression of myocardin transcriptional activity by Elk-1. (JPG 79 kb)

Supplementary Figure Legends and Methods (DOC 37 kb)

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Wang, Z., Wang, DZ., Hockemeyer, D. et al. Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression. Nature 428, 185–189 (2004). https://doi.org/10.1038/nature02382

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