Cellular Targets of Papillomavirus Oncoproteins

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The human papillomaviruses (HPVs) are associated with specific human cancers, most notably human cervical cancer. More than 100 different HPVs have now been described and approximately 25 of these are associated with lesions of the anogenital tract. These anogenital associated HPVs can be further subdivided into two groups on the basis of the clinical lesions with which they are associated. The "low risk" HPVs (e.g. HPV-6 and HPV- 11) are associated with benign genital warts or condyloma acuminata that only very rarely progress to cancers, whereas the "high risk" HPVs (e.g. HPV16 and HPV18) are associated with intraepithelial neoplasias that can progress to cancer. Approximately 95% of human cervical cancers contain and viral DNA from a "high risk" HPV type and express the HPV E6 and E7 genes. This, along with independent molecular evidence, suggests strongly that the proteins encoded by the E6 and E7 genes of the "high risk" HPVs contribute directly to carcinogenic progression in the HPV positive cancers. The E7 proteins functions in cellular transformation, at least in part, through interactions with the product of the retinoblastoma susceptibility gene, pRB, and the other pRB related "pocket proteins". The major target of the E6 oncoprotein encoded by the genital tract, cancer associated human papillomaviruses is the p53 tumor suppressor protein. However, several lines of evidence indicate that these HPV E6 and E7 oncoproteins have additional cellular targets. Furthermore, the oncogenic bovine papillomavirus (BPV) E6 and E7 oncoproteins do not cause transformation by p53 and pRB dependent pathways. The specific aims of this project are designed to examine additional targets of the papillomavirus E6 and E7 proteins that may be important to their transformation functions. There are two major specific aims, one involving the E6 protein and the second the E7 protein. We will extend our studies on the HPV16 E6 protein targeting the ubiquitination and proteolysis of the C-terminal Src kinase (Csk) and the consequent activation of the Src family kinase Fyn. We have also initiated a proteomic screen using tandem affinity purification using BPV E7. We will explore the potential significance of the interaction of E7 with the microtubule-associated factor (MTAF600).