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Dualité fonctionnelle de LMP1 : implication dans l’apoptose et la transformation cellulaire

Abstract : Epstein-Barr virus (EBV) is a human herpesvirus that infects more than 90% of worldwide population, generally asymptomatically. However, numerous studies show that EBV promotes tumorigenesis. Indeed, EBV infection is associated with many human malignancies including Burkitt’s lymphoma, Hodgkin’s lymphoma and nasopharyngeal carcinoma. In most of these cancers associated with EBV, it expresses latency II program in which the latent membrane protein 1 (LMP1) is expressed. LMP1 is described as the major EBV oncogene because its expression is necessary in vitro for survival and proliferation of transformed cell lines. This membrane protein is functionally related to members of the TNF receptors superfamily. LMP1 is constitutively active and its expression leads to activation of NF-κB, PI3K and MAPK signaling pathways. These activation confers oncogenic properties to LMP1, however, toxic effects associated with its expression are also described. Indeed, LMP1 can induce cell death in different cell types. In this context, we first developed and characterized LMP1 derivative variants consisting of its C-terminal signal, complete or partial, fused to GFP. We show that these variants are able to sequester adaptors binding to LMP1 and TNFR1, and inhibit signal and phenotypes induced by them. These proteins have dominant negative effect and may counteract LMP1 transformant properties in latency II cellular models. In addition, these dominant negatives impair TNFR1 signaling and associated phenotypes. Then, we studied LMP1 properties outside infectious context and its involvement in epithelial transformation. We show that LMP1 induces cell death in MDCK epithelial cells, but some go beyond its cytotoxic effects generating lines stably expressing LMP1 and in which this viral oncogene promotes survival and exacerbates HGF-induced phenotypes. Ambivalent character of LMP1 could limit the oncogenic potential of EBV but in return support the emergence of cells resistant to apoptosis and able to enhance growth factor responses. Our work allowed us to better understand the functional duality of LMP1 on the one hand its oncogenic effects favoring cell survival and other pro-apoptotic properties, induced directly or reveal by its inhibition, limiting tumorigenesis. Thus, characterization of molecular mechanisms involving LMP1 could participate in the definition of potential therapeutic strategies for treating cancers associated with EBV and where LMP1 is expressed.
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Guillaume Brocqueville. Dualité fonctionnelle de LMP1 : implication dans l’apoptose et la transformation cellulaire. Médecine humaine et pathologie. Université du Droit et de la Santé - Lille II, 2011. Français. ⟨NNT : 2011LIL2S030⟩. ⟨tel-00769919⟩

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