TY - JOUR
T1 - 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
AU - Ghosh-Choudhury, Nandini
AU - Abboud, Sherry L.
AU - Mahimainathan, Lenin
AU - Chandrasekar, Bysani
AU - Choudhury, Goutam Ghosh
PY - 2003/6/13
Y1 - 2003/6/13
N2 - 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 MIEF-2A-mediated BMP-2 transcription. Furthermore expression of MEF-2A increased MHC expression in a PI 3-kinase-de. pendent 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.
AB - 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 MIEF-2A-mediated BMP-2 transcription. Furthermore expression of MEF-2A increased MHC expression in a PI 3-kinase-de. pendent 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.
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U2 - 10.1074/jbc.M302277200
DO - 10.1074/jbc.M302277200
M3 - Article
C2 - 12663654
AN - SCOPUS:0038159330
VL - 278
SP - 21998
EP - 22005
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 24
ER -