Abstract
The growth and differentiation factor bone morphogenetic protein-2 (BMP-2) regulates cardiac development during vertebrate embryogenesis. In cardiac precursor cells, BMP-2 has recently been shown to induce expression of cardiac transcription factors, including myocyte enhancer factor 2A (MEF-2A). The specific signal transduction mechanism by which BMP-2 regulates these actions is not known. We investigated the role of phosphatidylinositol (PI) 3-kinase in regulating these processes in cardiomyocyte precursor CL6 cells. BMP-2 increased PI 3-kinase activity in these cells in a time-dependent manner, resulting in increased expression of sarcomeric myosin heavy chain (MHC) and MEF-2A. Inhibition of PI 3-kinase abolished these actions of BMP-2, indicating the involvement of PI 3-kinase in these processes. Furthermore, BMP-2 stimulated specific protein.DNA complex formation when an MEF-2 DNA recognition element was used as probe. Antibody supershift assay confirmed the presence of MEF-2A in this protein.DNA complex. Inhibition of PI 3-kinase activity completely prevented the MEF-2A.DNA complex formation. BMP-2 also increased transcription of a reporter gene driven by an MEF-2-specific DNA element in a PI 3-kinase-dependent manner. Ectopic expression of MEF-2A increased BMP-2 transcription to the same extent induced by BMP-2, indicating that MEF-2A may participate in BMP-2 autoregulation in CL6 cells. Expression of dominant negative PI 3-kinase completely abolished BMP-2-induced as well as MEF-2A-mediated BMP-2 transcription. Furthermore expression of MEF-2A increased MHC expression in a PI 3-kinase-dependent manner. Together these data provide the first evidence that BMP-2-induced PI 3-kinase signaling regulates MEF-2A expression and define a mechanism of MEF-2A-dependent BMP-2 transcription.
Highlights
The growth and differentiation factor bone morphogenetic protein-2 (BMP-2) regulates cardiac development during vertebrate embryogenesis
myocyte enhancer factor 2A (MEF-2A) Induces Formation of Mature Cardiomyocyte-expressing myosin heavy chain (MHC)—Because MEF-2A regulates BMP-2 expression and BMP-2 is necessary for differentiation of CL6 cells to form mature cardiomyocytes [16], we examined the effect of MEF-2A expression on this process
The present study shows that, in cardiomyocyte precursor cells, BMP-2 activates PI 3-kinase
Summary
21998 –22005, 2003 Printed in U.S.A. Phosphatidylinositol 3-Kinase Regulates Bone Morphogenetic Protein-2 (BMP-2)-induced Myocyte Enhancer Factor 2A-dependent Transcription of BMP-2 Gene in Cardiomyocyte Precursor Cells*□S. The growth and differentiation factor bone morphogenetic protein-2 (BMP-2) regulates cardiac development during vertebrate embryogenesis. BMP-2 has recently been shown to induce expression of cardiac transcription factors, including myocyte enhancer factor 2A (MEF-2A). BMP-2 increased transcription of a reporter gene driven by an MEF-2specific DNA element in a PI 3-kinase-dependent manner. BMP-2induced expression and DNA binding of MEF-2 transcription factor are dependent upon PI 3-kinase activity. In addition we show that BMP-2-induced PI 3-kinase activity regulates MEF2-dependent reporter gene transcription. PI 3-kinase Regulates BMP-2 Gene in Cardiomyocyte Precursor Cells strate that BMP-2-induced BMP-2 gene transcription is regulated by MEF-2 in a PI 3-kinase-dependent manner
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