Cell cycle regulation and myocyte hypertrophy

University Of California San Francisco, San Francisco CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The overall goal is to understand cell cycle control of cell division and growth during cardiovascular development and disease. The goal for this proposal is to elucidate the role of eel cycle regulators in hypertrophic response. The specific aims of this proposal are to test the hypotheses that: 1) the activity of Cdk4-cyclin D1 complexes is precisely regulated by p21 during the hypertrophic response; 2) phosphorylated Rb regulates hypertrophy through its interaction with chromatin remodeling factors, SWI/SNF, and histone deacetylases, (HDACs); and 3) a subset of target genes of the E2F-1 is activated in response to hypertrophic signals. To achieve these goals, an in vitro model of hypertrophy in Angiotensin II (AngII)-treated C2C12 myoblasts will be used. The first hypothesis will be tested by overexpressing wild type and truncated mutants of p21, as well as an antisense p21 construct, and measuring Cdk4 kinase activity and DNA/protein synthesis in AngII-treated myoblasts. The second will be tested by co-immunoprecipitation of HDAC and SWI/SNF with Rb and subsequent immunoblot. Other proteins that associate with or dissociate from Rb complex during hypertrophic response will be identified using mass spectrometry. The hypothesis will be tested by screening microarrays with probes derived from quiescent and AngII-treated C2C12 cells to identify E2F target gene, activated in hypertrophic response, and immunoblot and Northern analyses of those activated genes. These studies will provide insight into the mechanisms of cell growth that occur during normal and pathologic hypertrophy. [unreadable] [unreadable]