Apoptosis Regulation by Adenovirus and Cellular Genes

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DESCRIPTION (provided by applicant): In virus-infected cells, the process of apoptosis serves as a cellular defense mechanism to restrict viral replication and pathogenesis. Infection with human adenoviruses (Ad) results in productive infection of epithelial cells while infection of lymphoid cells results in quiescent infection. Studies on Ad-infected epithelial cells have revealed several key regulatory events of the Ad apoptosis program, but many important checkpoints remain to be illuminated. The activities of the E1A oncogene that modulate the cell cycle through interaction with cell cycle regulatory proteins and facilitate viral replication also contribute to the onset of apoptosis in infected cells. The E1B-19K protein, a member of the vBCL-2 family proteins plays a dominant role in suppression of apoptosis. This present renewal proposal will investigate how viral genes modulate the core cellular apoptotic machinery in epithelial cell models. Aim 1 will identify which of the BH3-only Bcl-2 family effector proteins is activated during Ad-infection and establish its role in virus-induced apoptosis. Aim 2 will investigate the link between the anti-apoptotic activity of E1B-19K and complex formation with BH123 family proteins BAK and BAX. This aim will also investigate if an N-terminally processed form of BAX is involved in amplification of Ad-induced apoptosis. Aim 3 will study modulation of a direct apoptotic activity of the cytoplasmically targeted form of p53 by E1B-19K. Aim 4 will investigate the role of various caspases and apoptotic endonucleases in Ad-induced apoptosis. Our studies would employ a combination of genetic and biochemical approaches to identify the critical regulatory steps in Ad-induced apoptosis. Our proposed studies will increase our understanding of the mechanism by which viral genes EIA and E1B-19K modulate the activities of cellular Bcl-2 family genes and identify potential targets for intervention in the viral apoptosis paradigm.