Cooperative roles of Tat & k-cyclin in Kaposi's sarcoma

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DESCRIPTION (provided by applicant): Kaposi's sarcoma is a malignant tumor of endothelial origin and the most frequent cancer in AIDS patients. Sixty percent of AIDS-associated KS initiate in the oral cavity, representing a serious problem in oral health. Despite identification of human Herpesvirus 8 (HHV-8) as the etiological agent for all forms of KS, the extraordinarily higher prevalence of KS in HIV-infected patients suggests a cooperative interaction between HIV and HHV-8 in the development of KS. HIV Tat is one of the key regulating factors for viral gene expression and plays many roles in HIV-associated pathogenesis. Tat causes dysfunction and transformation of cultured endothelial cells and induces KS-like lesions in transgenic animals. HHV-8 k-cyclin, a homologue of cellular cyclin D, disrupts cell growth control by aberrantly activating Cdk6 and accelerating the G1/S transition of the cell cycle. The expression of k-cyclin promotes proliferation of endothelial cells. We have found that Tat interacts with k-cyclin in vivo, providing evidence of pathological links between HIV and HHV-8. Here, we propose to study the cooperative roles of Tat and k-cyclin in the development of KS by using immortalized primary endothelial cells. Using this in vitro model, we will dissect steps that are responsible for the HHV-8-infected endothelial cells to progress toward the development of KS malignancy. The specific aims are: (1) define the molecular interaction between Tat and k-cyclin and examine kinase activities associated with these two proteins, (2) determine cooperative effects of Tat and k-cyclin in promoting the proliferation of endothelial cells, (3) demonstrate roles of Tat in enhancing HHV-8 infection and HHV-8-induced cell transformation. These studies will increase our understanding of the pathogenesis of AIDS-associated KS, the cooperative role of Tat and k-cyclin, and suggest a strategy in combating this tumor.