Pro-oncogenic roles of apoptotic caspases

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DESCRIPTION (provided by applicant): Apoptosis is normally considered a barrier for carcinogenesis because of its roles in getting rid of unwanted or damaged cells. However recent discoveries in our laboratory suggest that we need to re-examine the roles of apoptosis, especially those of apoptotic caspases, in carcinogenesis. In this project, we will examine the hypothesis that non-lethal caspase 3 or 7 activation induces genomic instability to facilitate radiation and other stress-induced carcinogenesis. Our hypothesis is a bold one that goes against the current paradigm. It will have wide-ranging implications since many endogenous and external stimuli could activate apoptotic caspases. Examples of such stimuli include exposure to ionizing radiation, UV, chemicals, and oncogene expression (e.g., myc). A facilitative role for caspases in carcinogenesis would provide exciting new insights into how those diverse environmental insults cause cancer. We will use a variety of in vitro and in vivo models, in combination with state-of-the-art molecular technologies, to examine the roles of caspases 3&7 in radiation- and other stress-induced genetic instability and carcinogenesis. We expect our studies to provide a comprehensive evaluation of the roles of caspases 3&7 in promoting carcinogenesis through inducing genetic instability. Upon completion of the project, we hope we can gain significant insights into the roles of apoptotic caspases in carcinogenesis. Such insights may provide novel targets for future cancer prevention strategies.