Mechanisms of Oncogenesis by Gammaherpesvirus

Epstein-Barr virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV) are associated with a number of human malignancies. These include Burkitt's lymphoma, nasopharyngeal carcinoma, Hodgkin's lymphoma, breast carcinoma, Kaposi's sarcoma and body cavity based lymphoma. We are investigating the fundamental mechanisms utilized by these gammaherpesviruses to induce cell mediated growth transformation. We are using genetics, genomics and biochemical approaches to establish unknown pathways involved in these cellular events and attempting to develop models that explain how gammaherpesviruses establish transformation in human cells.

EBV infects human B-lymphocytes and is the etiological agent of infectious mononucleosis. In vitro EBV efficiently growth transforms primary B-lymphocytes. Studies have demonstrated that only a subset of the viral latent genes is essential for EBV mediated transformation. One such gene is the EBV nuclear antigen EBNA3C. EBNA3C is a large nuclear transcription factor involved in modulating transcription activated by a cellular repressor RBP-Jkappa and other transcription factors. We are interested in other related functions of EBNA3C through its interactions with a number of other cellular molecules. Screens to identify other cellular targets have identified a number of interesting targets associated with EBNA3C. These molecules are involved in cell division, metastasis, apoptosis, cell cycle regulation and regulation of protein degradation. We are currently pursuing a number of these molecules in an effort to demonstrate their biochemical, structural and functional relevance in human cancers.

KSHV is the second human oncogenic herpesvirus, associated with Kaposi's sarcoma (KS) and pleural effusion lymphomas (PELs) or body cavity based lymphomas (BCBLs). KSHV also belongs to the human gammaherpesvirus family with collinear homology to EBV. KSHV infects human B-cells and endothelial cells. The mechanism of KSHV mediated oncogenesis is not understood. Our laboratory is involved in the elucidation of the mechanisms by which KSHV persists and establishes persistent infection in the associated human cancers.

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