| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2001: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 2000: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Research Abstract |
The aims of basic research for understanding the molecular mechanism of cardiomyocyte differentiation and cardiac development include the establishment of the genetic technique by which cardiomyocyte differentiation can be induced, which may contribute to the practical therapeutic application for tissue regeneration and the subsequent gene-therapy for heart failure. From this respect, we investigated the molecular mechanism by which cardiomyocyte differentiation is regulated by using a cardiomyogenic cell line, P19CL6, which can differentiate efficiently into beating cardiomyocytes.
We previously demonstrated that bone morphogenetic proteins (BMPs) induce cardiornyocyte differentiation through the MAPKKK TAK1. Transcription factors Smads have been reported to play a critical role in BMP signaling and the ATF/CREB family transcription factor ATF-2 has recently been shown to be a common nuclear target of the Smad and the TAK1 pathways. We here examined whether Smads and ATF-2 are involved
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in cardiomyocyte differentiation using P19CL6, a clonal derivative of murine P19 cells. Although P19CL6 efficiently differentiates into cardiomyocytes when treated with dimethyl sulfbxide, P19CL6noggin, a P19CL6 cell line constitutively overexpressing the BMP antagonist noggin, did not differentiate into cardiomyocytes. Co-overexpression of Smadl, a ligand-specific Smad, and Smad4, a common mediator Smad, restored the ability of P19CL6noggin to differentiate into cardiomyocytes, whereas stable overexpression of Smad6, an inhibitory Smad, completely blocked differentiation of P19CL6, suggesting that the Smad pathway is necessary for cardiomyocyte differentiation. ATF-2 stimulated βMHC promoter acitvity by the synergistic manner with Smad1/4 and TAK1, while overexpression of the dominant negative form of ATF-2 reduced the promoter activities of several cardiac-specific genes and inhibited cardiomyocyte differentiation of P19CL6. These results suggest that Smads, TAK1, and their common target ATF-2 cooperatively play a critical role in cardiomyocyte differentiation. Less
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