This proposal seeks continued support for our studies examining the mechanisms by which the E7 proteins of genital human papillomaviruses (HPV) contribute to the pathogenesis of viral infections, in anogenital cancers, the E6 and E7 genes of the high risk viruses are selectively retained and expressed implicating their products as oncoproteins. Epithelial cells immortalized by E6 and E7 also exhibit altered differentiation capabilities in raft cultures similar to those seen in neoplasias in vivo. The mechanisms by which these viral oncoproteins immortalize and alter the differentiation capabilities of epithelial cells involves the binding of host proteins involved in cell-cycle regulation. The E7 protein binds the retinoblastoma gene product (Rb) as well as the related p107 and p130 proteins. The binding of E7 to Rb and p107 alters the regulation of E2F mediated transcription. In the current funding period we have demonstrated an important role for E7 in the productive viral life cycle by acting to facilitate the maintenance of viral episomes. Furthermore, our recent studies have determined that the interaction between E7 and histone deacyelases (HDACs) is important for extension of life span and episomal maintenance. In this renewal application, I propose to investigate the importance of E7 interactions with Rb family members as well as HDACs in the viral life cycle and to dissect the mechanisms by which E7 blocks cell cycle exit during differentiation. We will ask the following questions: 1). What are the effects of E7-Rb binding as well as E7-HDAC interactions on the loading of transcription factors on S-phase specific promoters in undifferentiated and differentiated cells? Do the E7-HDAC complexes activate or repress E2F-inducible genes? 2). What are the effects of Rb, p130 and p107 during the differentiation dependent late phase of the viral life cycle? Does abrogation of Rb, p130 and p107 by siRNA mimic the effects of E7 on these activities. 3). What is the effect of interactions with Rb, p130 p107 and HDACs on the functions of low risk E7 protein in the viral life cycle? Are there any novel interacting partners of HPV 11 E7?
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