Transforming Growth Factor-β1and Protein Kinase C Synergistically Activate the c-fosSerum Response Element in Myocardial Cells

We previously reported that transforming growth factor-β1(TGF-β1) potentiatedα1-adrenergic and stretch-induced c-fosmRNA expression and norepinephrine (NE)-induced amino acid incorporation in rat cultured myocardial cells (MCs). In the present study, we attempted to explore the mode of TGF-β1action for c-fosgene expression in MCs. In the transient transfection assay, TGF-β1potentiated NE- or 12-O-tetradecanoylphorbol-13-acetate (TPA)-activated c-fospromoter/enhancer, but not forskolin-activated c-fospromoter/enhancer. The c-fosserum response element (SRE) and the TPA response element (TRE) were responsible for TGF-β1-induced potentiation of the NE or TPA action. Although TGF-β1activated not only the wild-type c-fosSRE, but also the mutated c-fosSRE, which contains an intact binding site for the serum response factor (SRF) but lacks the ternary complex factor (TCF) binding site, TPA activated the wild-type c-fosSRE but not the mutated c-fosSRE. TGF-β1did not potentiate the effects of TPA on the activation of mitogen-activated protein kinase (MAPK) and the phosphorylation of Elk-1 and SAP-1a, which belong to TCF at the c-fosSRE. These results indicate that TGF-βfpotentiates the c-fosSRE activated by PKC through the SRF binding site. TGF-β1is involved in the regulation of c-fosgene expression through the c-fosSRE and is subsequently involved in the regulation of the gene which has the TRE in the promoter/enhancer region.