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Abstract
Grant Number: 2R37CA012055-31 Project Title: Studies of Epstein-Barr Virus
PI Information: Name Title MILLER, I. GEORGE. george.miller@yale.edu PROFESSOR Abstract: DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV)is etiologically associated with many cancers, including nasopharyngeal cancer, Hodgkin's and non-Hodgkin's lymphoma, and Burkitt's lymphoma. The virus remains in a state of limited gene expression in all EBV-associated tumors and in B cells of healthy infected persons. Reactivation into the viral lytic cycle is required for cell to cell spread and transmission among individuals. The bZIP protein, ZEBRA, encoded in the EBV BZLF1 gene, mediates the switch between latency and lytic cycle. The global objective of the proposal is to understand ZEBRA's mechanism of action and regulation of expression. Experiments concerning the function of ZEBRA will analyze consequences of mutations in ZEBRA's basic domain on conformation, protein-protein interactions and capacity to alter chromatin on target promoters. The role of phosphorylation in regulation of ZEBRA's action, particularly as a repressor of late viral promoters will be investigated. Experiments that explore control of expression of BZLF1 will address the question whether open chromatin configuration is sufficient to activate Zp, the BZLF1 promoter. The novel hypothesis that CpG methylation downstream of Zp may regulate BZLF1 expression will be pursued. The potential role of cellular Oct 1 as an inhibitor of Zp autostimulation will be examined. The proposed experiments, utilizing molecular genetics and biochemistry, are integrated into the biology of the virus and address several seminal unresolved issues about the pathogenesis of this human cancer virus.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
Epstein Barr virus, latent virus infection, protein structure function, virus genetics, virus protein, virus replication
DNA methylation, acetylation, conformation, gene expression, genetic promoter element, histone, host organism interaction, phosphorylation, point mutation, protein protein interaction
immunoprecipitation
Institution: YALE UNIVERSITY 47 COLLEGE STREET, STE 203 NEW HAVEN, CT 065208047 Fiscal Year: 2003 Department: PEDIATRICS Project Start: 01-JAN-1979 Project End: 31-MAR-2008 ICD: NATIONAL CANCER INSTITUTE IRG: EVR