Expression of the Epstein–Barr virus latent membrane protein 1 induces B cell lymphoma in transgenic mice

Abstract

The latent membrane protein 1 (LMP1) of the Epstein-Barr virus has transforming properties in rodent fibroblasts and is expressed in most of the cancers associated with Epstein-Barr virus (EBV) infection including posttransplant lymphomas, Hodgkin's disease, nasopharyngeal carcinoma, and AIDS-related lymphomas. In this study, three lineages of LMP1 transgenic mice were established with LMP1 expressed under the control of the Ig heavy chain promoter and enhancer. Lymphoma developed in all three lineages, and the incidence of lymphoma increased significantly with age with lymphomas developing in 42% of transgenic mice over 18 months. The expression of LMP1 was detected at high levels in the lymphoma tissues but only at trace levels in normal lymphoid tissues. Gene rearrangement of the Ig heavy chain indicated monoclonality or oligoclonality in all lymphomas, some of the lymphoid hyperplastic spleens, and some histologically normal spleens. These data reveal that LMP1, without the expression of other EBV genes, is oncogenic in vivo and indicate that LMP1 is a major contributing factor to the development of EBV-associated lymphomas.

Roles of TNF Receptor-Associated Factor 3 in Signaling to B Lymphocytes by Carboxyl-Terminal Activating Regions 1 and 2 of the EBV-Encoded Oncoprotein Latent Membrane Protein 1

“…It has been shown previously that only the CCT of LMP1 is required for postaggregation delivery of signals, and that LMP1 signals similarly in both human and mouse B cells (7,8,14,15,33). To study LMP1 signaling, we have previously generated a chimeric molecule (hCD40LMP1) composed of the extracellular and transmembrane domains of hCD40 and the CCT of LMP1.…”

“…Latent membrane protein (LMP)1 is the only EBV-encoded protein that can transform rodent fibroblasts and render them tumorigenic in nude mice (4 -6). Transgenic mice expressing LMP1 under the control of the mouse IgH enhancer and a V H promoter develop B cell lymphomas at an accelerated rate as they age (7). A large number of published studies indicate that LMP1 is a major contributing factor to the development of EBV-associated lymphoproliferative disease and lymphomas (1-3, 5, 8).…”

Epstein–Barr virus-encoded latent infection membrane protein 1 regulates the processing of p100 NF-κB2 to p52 via an IKKγ/NEMO-independent signalling pathway

“…Among these viral proteins, the latent infection membrane protein 1 (LMP1) has attracted much attention because of its ability to transform rodent fibroblast cell lines and drive the immortalization of primary human B lymphocytes in vitro (Kaye et al, 1993). Moreover, targeted expression of LMP1 in the Bcell or epithelial compartment of transgenic mice results in oncogenesis (Wilson et al, 1990;Kulwichit et al, 1998).…”

Ubiquitination of the Epstein–Barr virus-encoded latent membrane protein 1 depends on the integrity of the TRAF binding site

“…Taken together, our results suggest that TRAF proteins are involved in the ubiquitination of LMP1, and that their binding to LMP1 may facilitate their own ubiquitination. Oncogene (2003Oncogene ( ) 22, 5614-5618. doi:10.1038 Keywords: LMP1; ubiquitin; TRAF3; lipid rafts The latent membrane protein 1 (LMP1), encoded by the Epstein-Barr virus (EBV), was identified as an oncogene because of its capacity to transform rodent fibroblast cell lines in culture (Wang et al, 1985;Baichwal and Sugden, 1988) and to induce lymphomas in transgenic mice (Kulwichit et al, 1998). LMP1 is expressed in tumor cells from several human malignancies associated with EBV, such as nasopharyngeal carcinoma, Hodgkin's disease and other atypical lymphoproliferative disorders, suggesting that this oncoprotein plays a determinant role in the pathogenesis of these diseases.…”