The Epstein-Barr virus (EBV) is closely associated with human malignancies which develop in both lymphoid and epithelial cells. The goal of this research program is to determine the role of EBV in the genesis of malignancy and to characterize the viral genes which contribute to oncogenesis. Work from our laboratory has analyzed EBV expression in epithelial and lymphoid malignancies. The EBV nuclear antigen, EBNA 1, the membrane proteins, LMP 1 and LMP 2, and a previously undescribed gene from the BamHI A rightward open reading frame O (BARF O) are consistently transcribed in nasopharyngeal carcinoma (NPC) and parotid carcinoma whereas in some lymphomas, LMP1 and LMP2, EBNAs 1-6, an BARFO may be transcribed. In Burkitt's Lymphomas only EBNA1 is thought to be expressed. It is likely that EBV alters cellular growth in a complex manner which may involve interaction of several cellular types and synthesis of growth factors and interleukins. This type of cellular interaction cannot be duplicated in assays in vitro. Transgenic mice provide an opportunity to asses the effects of individual viral genes in the context of the entire organism. In addition, some of the viral genes may function in a cell-type specific manner. The ability to target expression in transgenic mice to specific tissues provides the opportunity to assess the cell-specific effects of expression of the viral genes. The guiding hypothesis is that EBV genes directly alter cell growth and contribute to oncogenesis. To express the EBV transforming gene, LMP1, and the associated integral membrane protein, lMP2, in the appropriate cell types, transgenic mice lineages have been established containing the lMP1 and LMP2 genes under the control of the immunoglobulin promoter/enhancer (IG). The expression of the genes will be assessed through analysis of RNA and protein. Mice transgenic for both lMP1 and lMP2 will be produced by cross-breeding. The growth properties of the B lymphocytes will be assessed in vitro and in SCID mice. To develop a model of latent transforming EBV infection in epithelial cells, the k14 keratin promoter will be used to target expression to the basal epithelium. Transgenic lineages expressing lMP1 and LMP2 under the control of the k14 promoter will be developed and analyzed for expression of the viral genes, altered growth properties, and histopathology. Finally, to identify activation pathways which complement LMP1 and LMP2 expression, EBV transgenic mice will be bred to mice expressing specific cellular oncogenes in lymphoid and epithelial cells.
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