REGULATION OF APOPTOSIS BY VIRAL TRANSFORMING PROTEINS

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Adenovirus encodes two genes involved in transformation, E1A and E1B, which cooperate to transform primary rodent cells.The E1A gene products stimulate cell proliferation but fail to transform cells alone due to the induction of programmed cell death (apoptosis). Expression of the E1B gene or the human bcl-2 proto-oncogene, blocks E1A-induced cell death to produce transformation with high efficiency. The E1B gene encodes two products the l9K and 55K proteins that are unique proteins. Both of these proteins enhance transformation by E1A by blocking induced cell death. Additionally, the E1B 19K protein can block apoptosis induced by tumor necrosis factor-a (TNF-a) and anti-Fas antibodies. Recent results from Dr. White's laboratory has shown that the E1A proteins induce p53 which in turn induces apoptosis. The E1B 55K protein directly binds p53 and presumably interferes with it's function like SV40 T antigen. The mechanism of action of the E1B l9K protein in suppression of p53 is unknown. The aim of this proposal is to ascertain the mechanism by which apoptosis by p53 is regulated. The approach is to define how E1A, c-myc, TNF-a, and anti-Fas antibodies induce p53 and apoptosis and how the E1B l9K and bcl-2 proteins block this effect.