We propose to continue our analysis of the molecular mechanisms underlying the transforming activity of bovine papillomavirus. The papillomaviruses are small DNA viruses that induce benign tumors that occasionally progress to malignant lesions. The human papillomaviruses (HPV) cause a number of human proliferative diseases, and there is a strong association between HPV infection and cervical and other carcinomas. The animal fibropapillomaviruses genetically resemble the HPV yet display different tissue specificity, and readily induce morphologic transformation of established rodent fibroblast cell lines. This project will focus on the BPV E5 protein which we have identified as the major viral transforming protein. During the current grant period we discovered that the E5 protein causes the rapid and specific activation of intracellular PDGF receptors in fibroblasts, and we have proposed that the activated receptor initiates a series of events that culminate in cell proliferation and morphologic transformation. We will carry out genetic and biochemical tests of this model that the E5 protein transforms cells by activating this cellular protein. The mechanism by which the E5 protein activates the PDGF receptor will also be examined with particular attention paid to testing our hypothesis that the E5 protein and the PDGF receptor associate. Temperature sensitive and dominant negative E5 mutants will be isolated and used to examine in more detail the mechanism of action of this protein. Finally, we will extend our interesting discovery that the BPV E5 gene can cause tumorigenic transformation of murine keratinocytes. It is our strong belief that continued comprehensive analysis of viral oncogenes will continue to shed light on normal and abnormal host cell processes and may provide insight into the pathogenesis of human diseases.
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