Epstein-Barr virus (EBV) is a human tumor virus that is etiologically associated with nasopharyngeal cancer, Burkitt's, Hodgkin's and immunoblastic lymphoma and other human cancers. In all EBV-associated tumors the virus remains in a latent state of limited gene expression. The virus must be reactivated into its lytic cycle in order to spread between cells and among individuals. The Rta protein encoded in the EBV BRLF1 gene plays an obligatory role in mediating the switch between latency and lytic cycle gene expression. Our global objectives are to understand the complex mechanism of action of Rta and the control of BRLF1 expression. The proposed experiments are derived from many recent publications and new original unpublished observations made in our laboratory about the nature of Rta response elements, the mechanism of synergy between Rta and ZEBRA, the existence of a DNA binding inhibitory domain on Rta, and the role of global CpG methylation and histone H3 and H4 acetylation modifications in control of the promoter of BRLF1. Accordingly our AIMS are: 1) To analyze the mechanism by which Rta directly activates some promoters. 2) To study the mechanism of synergy between Rta and ZEBRA. 3) To understand the mechanism of a DNA binding inhibitory domain of Rta and the functional role of post-translational modification of Rta. 4) To investigate the importance of CpG methylation. 5) histone modification, and 6) cellular and viral activators on the response of BRLF1 to lytic cycle inducing stimuli. The experimental emphasis is on analysis of viral gene expression in the context of the behavior of the intact viral genome in cultured B cell tumors. The studies proposed address fundamental, though complex, issues of regulation of gene expression through the combinational action of cellular and viral proteins.
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