The human DNA tumor virus adenovirus replicates productively in human cells and transforms primary rodent epithelial cells. Integral to these activities is the deregulation of cell cycle control and the inhibition of programmed cell death (apoptosis) by the viral oncogenes E1A and E1B. E1A induces S-phase, which is required for replication of viral DNA and stimulation of cell proliferation in transformation. E1A also induces apoptosis that it requires E1B to inhibit to sustain productive infection and permit oncogenic transformation. E1A deregulates the cell cycle by binding to and inhibiting negative regulators of cell growth, one of which is the retinoblastoma tumor suppressor gene product (Rb). E1B encodes two proteins that block apoptosis by binding to and inhibiting pro-apoptotic proteins: 55K binds and inhibits the p53 tumor suppressor protein;19K binds and inhibits Bax and other related pro-apoptotic components of the apoptotic machinery. I propose to extend these studies in two specific areas that center around the mechanism of modulation of death receptor signaling by E1A and E1B during infection of human cells, and the mechanism of inhibition of p53-dependent apoptosis downstream of mitochondria by the E1B 19K protein in rodent cells. Finally, mice mutant for known components on the apoptotic machinery will be utilized to establish the requirement and ordering of these gene products in cell death signaling pathways in viral infection and transformation. By executing these aims we hope to illuminate novel mechanisms of cell death regulation and how they relate to virus replication and the development of cancer. Knowledge gained from this approach will be useful in the development of new anti-viral and anti-cancer regimens.
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