Infections with specific high risk types of human papillomavirus (HPV) constitute a major risk factor for the development of precancerous and cancerous lesions of the uterine cervix. Laboratory studies suggest a mechanistic role of certain types of human papillomaviruses for the development of these lesions. As a consequence of the frequent integration of the HPV genome during carcinogenic progression, the only two viral proteins that are consistently expressed in the anogenital cancer are E6 and E7. They both have transforming properties in vitro, and together they are the only viral factors that are necessary for the immortalization of human genital keratinocytes. This proposal is focussed on the high risk HPV E7 genes, which encode zinc binding nuclear phosphoproteins of approximately 100 amino acid in size with structural and functional similarities to the adenovirus (Ad) E1A protein and the large tumor antigen of the simian virus 40 (SV40 TAg). Similar to these other DNA tumor virus oncoproteins, the high risk HPV E7 proteins exert at least part of their biological functions by interacting with and functionally inactivating the """"""""pocket proteins"""""""", a family of cellular regulators including the retinoblastoma tumor suppressor protein pRB, p 107 and p 130. Although the functional inactivation of the regulatory pathways governed by the pocket proteins may constitute one step in carcinogenesis, there are additional biological and biochemical properties of E7 that may be mediated by different pathways. This grant proposal seeks to uncover such cellular regulatory circuits by defining the molecular basis for two important biological functions of the HPV E7 protein. (1) I will determine the functional domains of the HPV E7 protein that are necessary for the immortalization of primary human genital epithelial cells, the normal host cells of the high risk HPVs. (2) I will define the molecular basis for the ability of HPV E7 to abrogate cell cycle checkpoint control. These proposed experiments are based on our preliminary results that suggest that E7 can interfere with the functions of the cell cycle kinase inhibitor p21cip1. Thus, the ultimate goal of the proposed studies is to identify and characterize on a molecular and biochemical level key regulatory processes that are subverted by an HPV infection and contribute to cellular immortalization and ultimately to carcinogenic progression. This will help the rational deign for intervention and prevention of HPV associated disease and cancer in the future.
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