The EBV latent membrane protein, LMP1, is essential for EBV-induced B lymphocyte transformation and it is expressed in nasopharyngeal carcinoma and Hodgkins Disease. LMP1 is an integral membrane protein that has pleiotropic effects on B lymphocytes and epithelial cells, many of which are mediated by alterations in cellular gene expression. This proposal will elucidate the biochemical events that mediate signal transduction by LMP1. A functionally important domain of LMP1 interacts with members of the TRAF family of cytoplasmic proteins that are implicated in signalling from members of the tumor necrosis factor receptor family. The amino acid sequence of LMP1 that is involved in interactions with TRAF proteins will be identified and characterized in detail. Competitive inhibitors for the interactions will be designed and tested for their effects on LMP1 signalling and the growth of EBV transformed cells. LMP1 mutants that are compromised in their interactions with the TRAF proteins will be tested for their transforming properties. Downstream effectors of the TRAF signalling pathway will be identified using the yeast two hybrid.
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