SIGNALING OF APOPTOSIS IN CANCER

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DESCRIPTION: Recent studies have demonstrated that tumor cells are more sensitive than normal cells to an apoptotic signal induced by a member of the tumor necrosis factor (TNF) family called TNF-related apoptosis- inducing ligand (TRAIL) also known as Apo2L. The applicant has made several interesting observations, including: (i) interferon gamma (INF- gamma) sensitizes A549, HT1090 and ME180 cancer cells to Apo2L-induced apoptosis; (ii) expression of transcription factor, INF regulatory factor (IFR-1), is also induced in these cells by INF-gamma; (iii) activation of Apo2L pathway activates specific caspases that induces cleavage of p120/Ras GTPase; and (iv) dexamethasone is a potent inhibitor of Apo2L-induced cell death. The goal of this application is to investigate the TRAIL/Apo2L pathway in tumor cells and define parts of the TRAIL/Apo2L signaling pathway that may lead to a better understanding the mechanisms underlying how cell killing of tumor cells occurs. Three Specific Aims are proposed: (I) to examine the mechanisms by which IRF-1 regulates the sensitization of tumor cells by IFN-gamma to the Apo2L-induced apoptosis; (II) to characterize the role of caspase-mediated cleavage of ras GAP during Apo2L-induced apoptosis; and (III) to determine the targets of dexamethasone's actions in the Apo2L pathway.