The overall goal of the proposed research is elucidation of the function of ras proteins in cell growth and differentiation. Similarities between the ras gene product (p21) and the G proteins suggest that p21 fucntions to transduce signals from membrane receptors to second messengers. However, the physiological and biochemical pathways in which p21 functions in vertebrate cells remain unknown. We will address the normal role of ras in selected cell systems to define the signal transduction pathway(s) in which p21 acts to elicit different biological responses. A major approach will employ a recently isolated ras mutant (M17) which appears to block normal ras function required for proliferation of NIH 3T3 cells. The mechanism by which M17 p21 blocks 3T3 cell growth will be analyzed with respect to progression through the cell cycle, response of quiescent cells to growth factors and changes in second messengers normally induced by growth factor stimulation. The effect of M17 mutants in rasH, rasK and rasN will be compared. These mutants will also be used to analyze the role of ras in signal transduction pathways leading to neuronal differentiation of PC12 cells and to investigate the potential activities of ras in differentiation of embryonal carcinoma cell lines. Induction of meiotic maturation of Xenopous oocytes by microinjection of p21 will be studied as an additional model to investigate second messenger systems in which ras may act as a coupling protein.
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