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Bone Morphogenetic Protein Signaling Modulates Myocardin Transactivation of Cardiac Genes

From the Department of Cell and Developmental Biology, Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill.

Correspondence to Da-Zhi Wang, PhD, Dept of Cell and Developmental Biology, 8340C MBRB, 103 Mason Farm Rd, Chapel Hill, NC 27599-7126. E-mail dawang{at}med.unc.edu

Bone morphogenetic proteins (BMPs) play important roles in cardiovascular development. However, how BMP-signaling pathways regulate cardiac gene expression is less clear. We have previously identified myocardin as a cardiac and smooth muscle-specific transcriptional cofactor for serum response factor (SRF). Myocardin potently activates target gene expression by tethering with SRF bound to SRF-responsive elements, the CArG box. Here, we show that Smad1, an effector of the BMP-signaling pathway, synergistically activates myocardin-dependent cardiac gene expression. Interestingly, the CArG box is necessary and sufficient to mediate such synergy, whereas no obvious Smad-binding element appears to be involved. Consistent with their functional interaction, we find that myocardin and Smad1 proteins interact directly. Furthermore, myocardin protein levels were dramatically increased by BMP-2 treatment in cardiomyocytes. These findings suggest myocardin participates in a BMP signaling-dependent cardiac gene transcriptional program.

Key Words: myocardin • serum response factor • bone morphogenetic protein • Smad • cardiac gene expression

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