The Epstein-Barr virus (EBV) latent membrane protein (LMP1) is expressed in most of the malignancies associated with EBV and its expression in lymphoid and epithelial cell lines profoundly affects their biologic phenotype and gene expression. LMP1 is the only EBV gene that can transform immortalized rodent fibroblast lines to loss of contact inhibition, lower serum dependence, anchorage independence, and tumorigenicity in nude mice. LMP1 interacts with the tumor necrosis factor receptor (TNFR) associated factors (TRAFS) through which it activates the NFkB transcription factor and JNK kinase. We have generated three lineages of LMP 1 transgenic mice with LMP l expressed under the control of the heavy chain immunoglobulin promoter/enhancer. The mice have a 5 fold increase in the development of B cell lymphoma with LMP1 expressed at high levels in the lymphoma tissues. This result indicates that LMP1, without expression of other EBV genes, is oncogenic in vivo and suggests that LMP1 is a major contributing factor to the development of EBV-associated lymphomas. We have also 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 temperature sensitive mutants with regard to EGFR induction. Our preliminary data indicates that LMP1 also induces expression of the EGFR in rodent fibroblasts. In this grant, we will determine the biochemical basis of LMP1-mediated transformation and identify cellular genes that contribute to oncogenesis.
Our specific aims are to l) further characterize the transgenic lymphomas by identifying the molecular interactions of LMP1 and the activated signaling pathways, 2) determine if LMP1 expression in transgenic mice synergizes with activation of the nuclear oncogene, c-myc, 3) determine if inactivation of the tumor suppressor, p53, increases the malignant potential of LMP1 in transgenic mice, 4) characterize LMP l transformation of rodent fibroblasts by identifying the essential domains of LMP1 and the signaling pathways that are activated, 5) determine the contribution of EGFR induction by LMP1 to rodent fibroblast transformation using inhibitors of EGFR signaling and two temperature sensitive forms of LMP1.
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