Grants and Contracts Details
Description
Kaposi's sarcoma (KS) 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 HIVassociated
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.
Status | Finished |
---|---|
Effective start/end date | 6/1/05 → 5/31/08 |
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.