Abstract
Transgenic mice expressing Epstein–Barr virus (EBV) latent membrane protein 1 (LMP1) under the control of an immunoglobulin heavy-chain promoter and enhancer develop lymphoma at a threefold higher incidence than LMP1-negative mice. In vitro, LMP1 activates numerous signaling pathways including p38, c-Jun N terminal kinase (JNK), phosphatidylinositol 3 kinase (PI3K)/Akt, and NF-κB through interactions with tumor necrosis receptor-associated factors (TRAFs). These pathways are frequently activated in EBV-associated malignancies, although their activation cannot be definitively linked to LMP1 expression in vivo. In this study, interactions between LMP1 and TRAFs and the activation of PI3K/Akt, JNK, p38, and NF-κB were examined in LMP1 transgenic mice. LMP1 co-immunoprecipitated with TRAFs 1, 2, and 3. Akt, JNK, and p38 were activated in LMP1-positive and -negative splenocytes as well as LMP1-positive and -negative lymphomas. Multiple forms of NF-κB were activated in healthy splenocytes from LMP1 transgenic mice, in contrast to healthy splenocytes from LMP1-negative mice. However, in both LMP1-positive and -negative lymphomas, only the oncogenic NF-κB c-Rel, was specifically activated. Similarly to EBV-associated malignancies, p53 protein was detected at high levels in the transgenic lymphomas, although mutations were not detected in the p53 gene. These data indicate that NF-κB is activated in LMP1-positive healthy splenocytes; however, NF-κB c-Rel is specifically activated in both the transgenic lymphomas and in the rare lymphomas that develop in negative mice. The LMP1-mediated activation of NF-κB may contribute to the specific activation of c-Rel and lead to the increased development of lymphoma in the LMP1 transgenic mice.
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References
Andjelic S, Hsia C, Suzuki H, Kadowaki T, Koyasu S, Liou HC . (2000). J Immunol 165: 3860–3867.
Ardila-Osorio H, Clausse B, Mishal Z, Wiels J, Tursz T, Busson P . (1999). Int J Cancer 81: 645–649.
Arrand JR, Rymo L, Walsh JE, Bjorck E, Lindahl T, Griffin BE . (1981). Nucleic Acids Res 9: 2999–3014.
Baichwal VR, Sugden B . (1988). Oncogene 2: 461–467.
Ballerini P, Gaidano G, Gong JZ, Tassi V, Saglio G, Knowles DM et al. (1993). Blood 81: 166–176.
Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W et al. (1997). J Clin Invest 100: 2961–2969.
Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT . (1999). Oncogene 18: 3063–3070.
Chen W, Cooper NR . (1996). J Virol 70: 4849–4853.
Cogswell PC, Guttridge DC, Funkhouser WK, Baldwin Jr AS . (2000). Oncogene 19: 1123–1131.
Dawson CW, Tramountanis G, Eliopoulos AG, Young LS . (2003). J Biol Chem 278: 3694–3704.
Dempsey PW, Doyle SE, He JQ, Cheng G . (2003). Cytokine Growth Factor Rev 14: 193–209.
Devergne O, Cahir McFarland ED, Mosialos G, Izumi KM, Ware CF, Kieff E . (1998). J Virol 72: 7900–7908.
Devergne O, Hatzivassiliou E, Izumi KM, Kaye KM, Kleijnen MF, Kieff E et al. (1996). Mol Cell Biol 16: 7098–7108.
Durkop H, Foss HD, Demel G, Klotzbach H, Hahn C, Stein H . (1999). Blood 93: 617–623.
Edwards RH, Raab-Traub N . (1994). J Virol 68: 1309–1315.
Effert P, McCoy R, Abdel-Hamid M, Flynn K, Zhang Q, Busson P et al. (1992). J Virol 66: 3768–3775.
Eliopoulos AG, Blake SM, Floettmann JE, Rowe M, Young LS . (1999a). J Virol 73: 1023–1035.
Eliopoulos AG, Caamano JH, Flavell J, Reynolds GM, Murray PG, Poyet JL et al. (2003a). Oncogene 22: 7557–7569.
Eliopoulos AG, Gallagher NJ, Blake SM, Dawson CW, Young LS . (1999b). J Biol Chem 274: 16085–16096.
Eliopoulos AG, Waites ER, Blake SM, Davies C, Murray P, Young LS . (2003b). J Virol 77: 1316–1328.
Eliopoulos AG, Young LS . (2001). Semin Cancer Biol 11: 435–444.
Emmerich F, Meiser M, Hummel M, Demel G, Foss HD, Jundt F et al. (1999). Blood 94: 3129–3134.
Franken M, Devergne O, Rosenzweig M, Annis B, Kieff E, Wang F . (1996). J Virol 70: 7819–7826.
Fries KL, Miller WE, Raab-Traub N . (1996). J Virol 70: 8653–8659.
Gilmore TD, Cormier C, Jean-Jacques J, Gapuzan ME . (2001). Oncogene 20: 7098–7103.
Hammarskjold ML, Simurda MC . (1992). J Virol 66: 6496–6501.
Izumi KM, Cahir McFarland ED, Ting AT, Riley EA, Seed B, Kieff ED . (1999). Mol Cell Biol 19: 5759–5767.
Izumi KM, Kieff ED . (1997). Proc Natl Acad Sci USA 94: 12592–12597.
Kulwichit W, Edwards RH, Davenport EM, Baskar JF, Godfrey V, Raab-Traub N . (1998). Proc Natl Acad Sci USA 95: 11963–11968.
Laherty CD, Hu HM, Opipari AW, Wang F, Dixit VM . (1992). J Biol Chem 267: 24157–24160.
Levine AJ . (1997). Cell 88: 323–331.
Liebowitz D . (1998). N Engl J Med 338: 1413–1421.
Liu MT, Chang YT, Chen SC, Chuang YC, Chen YR, Lin CS et al. (2005). Oncogene 24: 2635–2646.
Miller WE, Cheshire JL, Raab-Traub N . (1998). Mol Cell Biol 18: 2835–2844.
Miller WE, Mosialos G, Kieff E, Raab-Traub N . (1997). J Virol 71: 586–594.
Moorthy RK, Thorley-Lawson DA . (1993). J Virol 67: 1638–1646.
Mosialos G, Birkenbach M, Yalamanchili R, VanArsdale T, Ware C, Kieff E . (1995). Cell 80: 389–399.
Murray PG, Flavell JR, Baumforth KR, Toomey SM, Lowe D, Crocker J et al. (2001). J Pathol 194: 158–164.
Niedobitek G, Agathanggelou A, Barber P, Smallman LA, Jones EL, Young LS . (1993). J Pathol 170: 457–461.
Nigro JM, Baker SJ, Preisinger AC, Jessup JM, Hostetter R, Cleary K et al. (1989). Nature 342: 705–708.
Pai S, O'Sullivan BJ, Cooper L, Thomas R, Khanna R . (2002). J Virol 76: 1914–1921.
Paine E, Scheinman RI, Baldwin Jr AS, Raab-Traub N . (1995). J Virol 69: 4572–4576.
Panagopoulos D, Victoratos P, Alexiou M, Kollias G, Mosialos G . (2004). J Virol 78: 13253–13261.
Stuntz LL, Busch LK, Munroe ME, Sigmund CD, Tygrett LT, Waldschmidt TJ et al. (2004). Immunity 21: 255–266.
Thornburg NJ, Pathmanathan R, Raab-Traub N . (2003). Cancer Res 63: 8293–8301.
Uchida J, Yasui T, Takaoka-Shichijo Y, Muraoka M, Kulwichit W, Raab-Traub N et al. (1999). Science 286: 300–303.
Wang D, Liebowitz D, Kieff E . (1985). Cell 43: 831–840.
Acknowledgements
We like to thank Dr Virginia Godfrey for histopathological diagnosis of lymphoma sections and Dr Elliot Kieff for the rabbit polyclonal anti-LMP1. This work was supported by National Institutes of Health Grant CA 19014 (to NR-T).
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Thornburg, N., Kulwichit, W., Edwards, R. et al. LMP1 signaling and activation of NF-κB in LMP1 transgenic mice. Oncogene 25, 288–297 (2006). https://doi.org/10.1038/sj.onc.1209023
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DOI: https://doi.org/10.1038/sj.onc.1209023
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