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Latent membrane protein 1 of Epstein–Barr virus coordinately regulates proliferation with control of apoptosis

Oncogene volume 24, pages 1711–1717 (2005)Cite this article

Abstract

Latent membrane protein 1 (LMP1), an oncoprotein encoded by Epstein–Barr virus (EBV), is an integral membrane protein, which acts like a constitutively active receptor. LMP1 is critical for some facet of EBV's induction and maintenance of proliferation of infected B cells. It, in part, mimics signaling by the CD40 receptor and has been implicated in regulating proliferation, survival, or both properties of EBV-infected cells. We established a conditional LMP1 allele in the context of the intact EBV genome to define the immediate-early cellular target genes regulated by LMP1 in order to assess its contributions to infected human B cells. The functional analysis of this conditional system indicated that LMP1 specifically induces mitogenic B-cell activation through c-myc and Jun/AP1 family members and confirms its direct role in upregulating expression of multiple genes with opposing activities involved in cell survival. LMP1's signals were found to be essential for the G1/S transition in human B cells; cells lacking LMP1's signals are cell cycle arrested and survive quiescently. LMP1's activities are therefore not required to maintain survival in nonproliferating cells. LMP1 does induce both pro- and antiapoptotic genes whose balance seems to permit survival during LMP1's induction and maintenance of proliferation.

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References

  • Anonymous (1997). Epstein–Barr Virus and Kaposi's Sarcoma Herpesvirus/Human Herpesvirus 8; International Agency for Research on Cancer. IARC: Lyon.

  • Ardila-Osorio H, Clausse B, Mishal Z, Wiels J, Tursz T and Busson P . (1999). Int. J. Cancer, 81, 645–649.

  • Babcock GJ, Decker LL, Volk M and Thorley-Lawson DA . (1998). Immunity, 9, 395–404.

  • Baichwal VR and Sugden B . (1988). Oncogene, 2, 461–467.

  • Brennan P, Floettmann JE, Mehl A, Jones M and Rowe M . (2001). J. Biol. Chem., 276, 1195–1203.

  • Briscoe J, Kohlhuber F and Müller M . (1996). Trends Cell Biol., 6, 336–340.

  • Cahir-McFarland ED, Carter K, Rosenwald A, Giltnane JM, Hendrickson SE, Staudt LM and Kieff E . (2004). J. Virol., 78, 4108–4119.

  • Chen G and Goeddel DV . (2002). Science, 296, 1634–1635.

  • Chen H, Hutt-Fletcher L, Cao L and Hayward SD . (2003). J. Virol., 77, 4139–4148.

  • Counter CM, Botelho FM, Wang P, Harley CB and Bacchetti S . (1994). J. Virol., 68, 3410–3414.

  • D'Souza B, Rowe M and Walls D . (2000). J. Virol., 74, 6652–6658.

  • Dadgostar H, Zarnegar B, Hoffmann A, Qin XF, Truong U, Rao G, Baltimore D and Cheng G . (2002). Proc. Natl. Acad. Sci. USA, 99, 1497–1502.

  • Delecluse HJ, Hilsendegen T, Pich D, Zeidler R and Hammerschmidt W . (1998). Proc. Natl. Acad. Sci. USA, 95, 8245–8250.

  • Dirmeier U, Neuhierl B, Kilger E, Reisbach G, Sandberg ML and Hammerschmidt W . (2003). Cancer Res., 63, 2982–2989.

  • Floettmann JE and Rowe M . (1997). Oncogene, 15, 1851–1858.

  • Fries KL, Miller WE and Raab-Traub N . (1996). J. Virol., 70, 8653–8659.

  • Gires O, Kohlhuber F, Kilger E, Baumann M, Kieser A, Kaiser C, Zeidler R, Scheffer B, Ueffing M and Hammerschmidt W . (1999). EMBO J., 18, 3064–3073.

  • Gires O, Zimber-Strobl U, Gonnella R, Ueffing M, Marschall G, Zeidler R, Pich D and Hammerschmidt W . (1997). EMBO J., 16, 6131–6140.

  • Hammerschmidt W and Sugden B . (2004). Trends Mol. Med., 10, 331–336.

  • Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, Kieff E and Rickinson A . (1991). Cell, 65, 1107–1115.

  • Higuchi M, Kieff E and Izumi KM . (2002). J. Virol., 76, 455–459.

  • Izumi KM and Kieff ED . (1997). Proc. Natl. Acad. Sci. USA, 94, 12592–12597.

  • Kastan MB, Zhan Q, el-Deiry WS, Carrier F, Jacks T, Walsh WV, Plunkett BS, Vogelstein B and Fornace Jr AJ . (1992). Cell, 71, 587–597.

  • Kaye KM, Izumi KM and Kieff E . (1993). Proc. Natl. Acad. Sci. USA, 90, 9150–9154.

  • Kaykas A, Worringer K and Sugden B . (2001). EMBO J., 20, 2641–2654.

  • Kaykas A, Worringer K and Sugden B . (2002). J. Virol., 76, 11551–11560.

  • Kieff E and Rickinson AB . (2001). Field's Virology, Vol. 2. Knipe DM, Howley PM, Griffin DE, Martin MA, Lamb RA, Roizman B and Straus SE (eds). Lippincott – Williams & Wilkins: Philadelphia, pp. 2511–2573.

    Google Scholar 

  • Kieser A, Kaiser C and Hammerschmidt W . (1999). EMBO J., 18, 2511–2521.

  • Kilger E, Kieser A, Baumann M and Hammerschmidt W . (1998). EMBO J., 17, 1700–1709.

  • Kisseleva T, Bhattacharya S, Braunstein J and Schindler CW . (2002). Gene, 285, 1–24.

  • Kulwichit W, Edwards RH, Davenport EM, Baskar JF, Godfrey V and Raab-Traub N . (1998). Proc. Natl. Acad. Sci. USA, 95, 11963–11968.

  • Laherty CD, Hu HM, Opipari AW, Wang F and Dixit VM . (1992). J. Biol. Chem., 267, 24157–24160.

  • Lam N and Sugden B . (2003). Cell Signal., 15, 9–16.

  • Lamb JA, Ventura JJ, Hess P, Flavell RA and Davis RJ . (2003). Mol. Cell, 11, 1479–1489.

  • Luftig M, Prinarakis E, Yasui T, Tsichritzis T, Cahir-McFarland E, Inoue J, Nakano H, Mak TW, Yeh WC, Li X, Akira S, Suzuki N, Suzuki S, Mosialos G and Kieff E . (2003). Proc. Natl. Acad. Sci. USA, 100, 15595–15600.

  • Moorthy RK and Thorley-Lawson DA . (1993). J. Virol., 67, 1638–1646.

  • Mori T, Anazawa Y, Iiizumi M, Fukuda S, Nakamura Y and Arakawa H . (2002). Oncogene, 21, 2914–2918.

  • Papa S, Zazzeroni F, Bubici C, Jayawardena S, Alvarez K, Matsuda S, Nguyen DU, Pham CG, Nelsbach AH, Melis T, De Smaele E, Tang WJ, D'Adamio L and Franzoso G . (2004). Nat. Cell Biol., 6, 146–153.

  • Qu L and Rowe DT . (1992). J. Virol., 66, 3715–3724.

  • Rickinson AB and Kieff E . (2001). Fields' Virology, Vol. 2. Knipe DM, Howley PM, Griffin DE, Martin MA, Lamb RA, Roizman B and Straus SE (eds). Lippincott – Williams & Wilkins: Philadelphia, pp. 2575–2627.

    Google Scholar 

  • Salghetti SE, Kim SY and Tansey WP . (1999). EMBO J., 18, 717–726.

  • Schuhmacher M, Kohlhuber F, Holzel M, Kaiser C, Burtscher H, Jarsch M, Bornkamm GW, Laux G, Polack A, Weidle UH and Eick D . (2001). Nucleic Acids Res., 29, 397–406.

  • Schultheiss U, Puschner S, Kremmer E, Mak TW, Engelmann H, Hammerschmidt W and Kieser A . (2001). EMBO J., 20, 5678–5691.

  • Shaulian E and Karin M . (2002). Nat. Cell Biol., 4, E131–E136.

  • Tamayo P, Slonim D, Mesirov J, Zhu Q, Kitareewan S, Dmitrovsky E, Lander ES and Golub TR . (1999). Proc. Natl. Acad. Sci. USA, 96, 2907–2912.

  • Tibbetts MD, Zheng L and Lenardo MJ . (2003). Nat. Immunol., 4, 404–409.

  • Uchida J, Yasui T, Takaoka-Shichijo Y, Muraoka M, Kulwichit W, Raab-Traub N and Kikutani H . (1999). Science, 286, 300–303.

  • Wan J, Sun L, Mendoza JW, Chui YL, Huang DP, Chen ZJ, Suzuki N, Suzuki S, Yeh WC, Akira S, Matsumoto K, Liu ZG and Wu Z . (2004). Mol. Cell. Biol., 24, 192–199.

  • Wang D, Liebowitz D and Kieff E . (1985). Cell, 43, 831–840.

  • Wilson JB, Weinberg W, Johnson R, Yuspa S and Levine AJ . (1990). Cell, 61, 1315–1327.

  • Yasui T, Luftig M, Soni V and Kieff E . (2004). Proc. Natl. Acad. Sci. USA, 101, 278–283.

  • Yin Y, Liu YX, Jin YJ, Hall EJ and Barrett JC . (2003). Nature, 422, 527–531.

  • Zhao R, Gish K, Murphy M, Yin Y, Notterman D, Hoffman WH, Tom E, Mack DH and Levine AJ . (2000). Genes Dev., 14, 981–993.

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Acknowledgements

This work was supported by SFB455 and by Grants Ha1354/3 and Ki825 from the Deutsche Forschungsgemeinschaft, by Public Health Service Grants P30CA14529, CA70723, and CA22443. BS is an American Cancer Society Research Professor.

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Authors and Affiliations

  1. Department of Gene Vectors, GSF-National Research Center for Environment and Health, Marchioninistr. 25, Munich, D-81377, Germany

    Ulrike Dirmeier, Ellen Kilger, Ute Schultheiss, Cinthia Briseño, Arnd Kieser & Wolfgang Hammerschmidt

  2. Department Bacteriology, Max-von-Pettenkofer-Institute, Munich, D-80336, Germany

    Reinhard Hoffmann

  3. Department of Otorhinolaryngology, Ludwig-Maximilians University, Munich, D-81377, Germany

    Olivier Gires

  4. Institute for Clinical Molecular Biology and Tumour Genetics, Munich, D-81377, Germany

    Dirk Eick

  5. McArdle Laboratory for Cancer Research, University of Wisconsin Medical School, Wisconsin, 53706, USA

    Bill Sugden

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  1. Ulrike Dirmeier
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  2. Reinhard Hoffmann
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Correspondence to Wolfgang Hammerschmidt.

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Dirmeier, U., Hoffmann, R., Kilger, E. et al. Latent membrane protein 1 of Epstein–Barr virus coordinately regulates proliferation with control of apoptosis. Oncogene 24, 1711–1717 (2005). https://doi.org/10.1038/sj.onc.1208367

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