Cardiac hypertrophy in response to load or agonists characteristically entails the induction of a so-called """"""""fetal"""""""" program of cardiac gene expression, superimposed on a generalized increase in cellular RNA and protein content. The signaling pathways involved in cardiac hypertrophy have been extensively studied, mostly in relation to the transcriptional induction of the fetal genes. However, upregulation of the fetal genes and total cellular protein are independent events. Hence, the signaling pathways mediating the latter effect remain largely unknown. Preliminary data suggest that the GTP binding protein Ras and its down stream effector Ras-GAP are involved in the upregulation of global gene expression. This was accompanied, and may be explained, by enhanced RNA polymerase 11 phosphorylation, and expression of its major kinase, cyclin dependent kinase 7 (cdk 7), in the cardiac myocytes.
The aims i n this proposal are: 1) To identify the functional domain(s) of Ras-GAP involved in mediating its effect on gene expression, and to use the yeast two hybrid system to identify its target proteins. 2) To test the functional importance of cdk7 for Ras and GAP-dependent signaling by engineering a dominant negative cdk 7. 3) To test the effect of Ras-GAP in vivo in a transgenic animal model over-expressing the protein in the heart. As a direct evaluation of the role of Ras in the development and maintenance of cardiac hypertrophy, the principal investigator will test the effect of the farnesyltransferase Ras inhibitor L-739,749 on the development and regression of cardiac hypertrophy in experimental rat models.
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