The goal of this research is to determine the role of EBV in the etiology of nasopharyngeal carcinoma (NPC), an epithelial malignancy that develops with high incidence in Southern China, Northern Africa, and among Eskimoes. The viral genes that are expressed in NPC include the latent membrane proteins, LMP1 and 2, and a family of mRNAs, transcribed through the BamHI A fragment, that potentially encode four previously unidentified proteins. LMP1 interacts with the tumor necrosis factor receptor (TNFR) associated factors (TRAFS) through which it activates the NfkappaB transcription factor and JNK kinase. We have shown that LMP1 induces the expression of epidermal growth factor receptor (EGFR) through the TRAF interacting domain and by mutating the TRAF interacting have produced two mutants that are temperature sensitive with regard to EGFR induction. We have determined that the two activation domains of LMP1 induce distinct forms of the NfkappaB transcription factor. We have also shown that LMP1 inhibits p53-mediated apoptosis through induction of A20. In this grant, we will further analyze the biochemical basis of LMP1-mediated transformation and the biologic and biochemical properties of LMP2 and the BamHI A proteins in epithelial cells.
Our specific aims are to 1) Characterize the signal transduction pathways activated by LMP1 in epithelial cells that activate distinct forms of NfkappaB and identify the cellular genes that are affected by these pathways, 2) Determine the effect of LMP1 and A20 expression on p53-mediated apoptosis, 3) Analyze LMP2 suppression in epithelial cells and identify the biochemical pathways affected by LMP2 expression, 4) Identify the proteins encoded by the BamHI A open reading frames in cell lines and in NPC tumors, 5) Determine the effect of the interaction of RK- BARF0 with Notch on Notch signaling, 6) Determine the effects of expression of the BamHI A proteins on viral and cellular expression.
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