The human papillomaviruses (HPVs) are associated with specific human cancers. Over 65 different HPVs have now been identified and over 20 of these are associated with genital tract lesions. The HPVs that are associated with genital tract lesions can be separated on the basis of their clinical associations into two distinct groups. One group, including HPV-6 and HPV-1 l, is generally associated with benign anogenital warts that infrequently progress to cancer and is considered """"""""low risk."""""""" The """"""""high risk"""""""" group, including HPV-16 and HPV-18, is associated with intraepithelial neoplastic lesions that are a comparatively high risk for malignant progression. The role the HPVs play in the progression of a benign HPV associated lesion to a cancer is likely.dude to the properties of the E6 and E7 viral oncoproteins expressed in the cancers as well as the preneoplastic lesions. The E6 and E7 genes of the high risk viruses encode oncoproteins which together can cooperate to efficiently immortalize primary human squamous epithelial cells, the normal host cell for the HPVs. she ability to immortalize primary keratinocytes is not a characteristic shared with the E6 and E7 genes of the low risk HPVs and it seems likely that this property may be linked to the oncogenic nature of the high risk HPVs. Insight into the mechanism by which these HPVs may be contributing to carcinogenic progression has come from the recognition that the oncoproteins encoded by these viruses and expressed in the cancers target and functionally inactivate key cell regulatory proteins, including the retinoblastoma and p53 tumor suppressor gene products. The E6 oncoprotein complexes with p53 and in doing so, stimulates its ubiquitination and proteolysis. The binding of E6 and p53 is mediated by an additional cell factor called E6- AP standing for E6-Associated Protein. The E6/E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. The studies proposed in this application are designed to further characterize the cellular proteins involved in the E6 mediated ubiquitination and degradation of p53.
The specific aims are to (i) further characterize the E6 associated protein; (ii) to determine additional proteins associated with E6-AP and with the E6/E6-AP complex; and (iii) to clone and characterize the mammalian UBC's involved in the E6 mediated degradation of p53.
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