The overall goal of this project is to elucidate the intracellular signalling pathways that control cell survival by preventing apoptosis. In the previous funding period, the applicant discovered that PI3 kinase was required for growth factor-dependent survival of several cell types. These observations were extended by the demonstration that the Ser/Thr kinase Akt is a key downstream effector of PI3 kinase in the cell survival pathway. Further studies have shown that apoptosis resulting from growth factor deprivation or inhibition of PI3 kinase is regulated by members of the Bcl-2 family and activation of ICE family proteases. In addition the oncoprotein MDM2 has been identified as a novel substrate for ICE family proteases and its proteolytic degradation may contribute to apoptosis by deregulation of p53. The applicant proposes to build upon these observations with the following four specific aims. (1) To determine whether GSK3, the only known physiological substrate of Akt, is involved in regulating cell survival. (2) To analyze the effects of PI3 kinase-induced signalling on members of the Bcl2 family. (3) To delineate the cascade of ICE proteases regulated by PI3 kinase signals and to determine whether Akt or downstream signalling molecules act to control protease activation. (4) To determine the biological role of MDM2 cleavage by apoptotic proteases in the cell death pathway.
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