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J Virol. Sep 1994; 68(9): 5602–5612.
PMCID: PMC236961

Upregulation of bcl-2 by the Epstein-Barr virus latent membrane protein LMP1: a B-cell-specific response that is delayed relative to NF-kappa B activation and to induction of cell surface markers.

Abstract

An ability of the Epstein-Barr virus latent membrane protein LMP1 to enhance the survival of infected B cells through upregulation of the bcl-2 oncogene was first suggested by experiments involving gene transfection and the selection of stable LMP1+ clones (S. Henderson, M. Rowe, C. Gregory, F. Wang, E. Kieff, and A. Rickinson, Cell 65:1107-1115, 1991). However, it was not possible to ascertain whether Bcl-2 upregulation was a specific consequence of LMP1 expression or an artifact of the selection procedure whereby rare Bcl-2+ cells already present in the starting population might best be able to tolerate the potentially toxic effects of LMP1. We therefore reexamined this issue by using two different experimental approaches that allowed LMP1-induced effects to be monitored immediately following expression of the viral protein and in the absence of selective pressures; activation of the NF-kappa B transcription factor and upregulation of the cell adhesion molecule ICAM-1 were used as early indices of LMP1 function. In the first approach, stable clones of two B-cell lines carrying an LMP1 gene under the control of an inducible metallothionein promoter were induced to express LMP1 in all cells. Activation of NK-kappa B and upregulation of ICAM-1 occurred within 24 h and were followed at 48 to 72 h by upregulation of Bcl-2. In the second approach, we tested the generality of this phenomenon by transiently expressing LMP1 from a strong constitutively active promoter in a range of different cell types. All six B-cell lines tested showed NF-kappa B activation in response to LMP1 expression, and this was followed in five of six lines by expression of ICAM-1 and Bcl-2. In the same experiments, all three non-B-cell lines showed NF-kappa B activation and ICAM-1 upregulation but never any effect upon Bcl-2. We therefore conclude that Bcl-2 upregulation is part of the panoply of cellular changes induced by LMP1 but that the effect is cell type specific. Our data also suggest that whilst NF-kappa B may be an essential component of LMP1 signal transduction, other cell-specific factors may be required to effect some functions of the viral protein.

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  • Aiello A, Delia D, Borrello MG, Biassoni D, Giardini R, Fontanella E, Pezzella F, Pulford K, Pierotti M, Della Porta G. Flow cytometric detection of the mitochondrial BCL-2 protein in normal and neoplastic human lymphoid cells. Cytometry. 1992;13(5):502–509. [PubMed]
  • Akbar AN, Borthwick N, Salmon M, Gombert W, Bofill M, Shamsadeen N, Pilling D, Pett S, Grundy JE, Janossy G. The significance of low bcl-2 expression by CD45RO T cells in normal individuals and patients with acute viral infections. The role of apoptosis in T cell memory. J Exp Med. 1993 Aug 1;178(2):427–438. [PMC free article] [PubMed]
  • Arenzana-Seisdedos F, Fernandez B, Dominguez I, Jacqué JM, Thomas D, Diaz-Meco MT, Moscat J, Virelizier JL. Phosphatidylcholine hydrolysis activates NF-kappa B and increases human immunodeficiency virus replication in human monocytes and T lymphocytes. J Virol. 1993 Nov;67(11):6596–6604. [PMC free article] [PubMed]
  • Baichwal VR, Sugden B. Transformation of Balb 3T3 cells by the BNLF-1 gene of Epstein-Barr virus. Oncogene. 1988 May;2(5):461–467. [PubMed]
  • Brattsand G, Cantrell DA, Ward S, Ivars F, Gullberg M. Signal transduction through the T cell receptor-CD3 complex. Evidence for heterogeneity in receptor coupling. J Immunol. 1990 May 15;144(10):3651–3658. [PubMed]
  • Cohen JI, Wang F, Kieff E. Epstein-Barr virus nuclear protein 2 mutations define essential domains for transformation and transactivation. J Virol. 1991 May;65(5):2545–2554. [PMC free article] [PubMed]
  • Cornelius LA, Taylor JT, Degitz K, Li LJ, Lawley TJ, Caughman SW. A 5' portion of the ICAM-1 gene confers tissue-specific differential expression levels and cytokine responsiveness. J Invest Dermatol. 1993 Jun;100(6):753–758. [PubMed]
  • Dawson CW, Rickinson AB, Young LS. Epstein-Barr virus latent membrane protein inhibits human epithelial cell differentiation. Nature. 1990 Apr 19;344(6268):777–780. [PubMed]
  • De Rossi A, Ometto L, Roncella S, D'Andrea E, Menin C, Calderazzo F, Rowe M, Ferrarini M, Chieco-Bianchi L. HIV-1 induces down-regulation of bcl-2 expression and death by apoptosis of EBV-immortalized B cells: a model for a persistent "self-limiting" HIV-1 infection. Virology. 1994 Jan;198(1):234–244. [PubMed]
  • de Wet JR, Wood KV, DeLuca M, Helinski DR, Subramani S. Firefly luciferase gene: structure and expression in mammalian cells. Mol Cell Biol. 1987 Feb;7(2):725–737. [PMC free article] [PubMed]
  • Fåhraeus R, Rymo L, Rhim JS, Klein G. Morphological transformation of human keratinocytes expressing the LMP gene of Epstein-Barr virus. Nature. 1990 May 31;345(6274):447–449. [PubMed]
  • Fennewald S, van Santen V, Kieff E. Nucleotide sequence of an mRNA transcribed in latent growth-transforming virus infection indicates that it may encode a membrane protein. J Virol. 1984 Aug;51(2):411–419. [PMC free article] [PubMed]
  • Finke J, Fritzen R, Ternes P, Trivedi P, Bross KJ, Lange W, Mertelsmann R, Dölken G. Expression of bcl-2 in Burkitt's lymphoma cell lines: induction by latent Epstein-Barr virus genes. Blood. 1992 Jul 15;80(2):459–469. [PubMed]
  • Gratama JW, Oosterveer MA, Zwaan FE, Lepoutre J, Klein G, Ernberg I. Eradication of Epstein-Barr virus by allogeneic bone marrow transplantation: implications for sites of viral latency. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8693–8696. [PMC free article] [PubMed]
  • Gregory CD, Dive C, Henderson S, Smith CA, Williams GT, Gordon J, Rickinson AB. Activation of Epstein-Barr virus latent genes protects human B cells from death by apoptosis. Nature. 1991 Feb 14;349(6310):612–614. [PubMed]
  • Gregory CD, Rowe M, Rickinson AB. Different Epstein-Barr virus-B cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line. J Gen Virol. 1990 Jul;71(Pt 7):1481–1495. [PubMed]
  • Grilli M, Chiu JJ, Lenardo MJ. NF-kappa B and Rel: participants in a multiform transcriptional regulatory system. Int Rev Cytol. 1993;143:1–62. [PubMed]
  • Hammarskjöld ML, Simurda MC. Epstein-Barr virus latent membrane protein transactivates the human immunodeficiency virus type 1 long terminal repeat through induction of NF-kappa B activity. J Virol. 1992 Nov;66(11):6496–6501. [PMC free article] [PubMed]
  • Hammerschmidt W, Sugden B. Genetic analysis of immortalizing functions of Epstein-Barr virus in human B lymphocytes. Nature. 1989 Aug 3;340(6232):393–397. [PubMed]
  • Henderson S, Rowe M, Gregory C, Croom-Carter D, Wang F, Longnecker R, Kieff E, Rickinson A. Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell. 1991 Jun 28;65(7):1107–1115. [PubMed]
  • Himes SR, Coles LS, Katsikeros R, Lang RK, Shannon MF. HTLV-1 tax activation of the GM-CSF and G-CSF promoters requires the interaction of NF-kB with other transcription factor families. Oncogene. 1993 Dec;8(12):3189–3197. [PubMed]
  • Hockenbery DM, Zutter M, Hickey W, Nahm M, Korsmeyer SJ. BCL2 protein is topographically restricted in tissues characterized by apoptotic cell death. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):6961–6965. [PMC free article] [PubMed]
  • Johnson GD, Davidson RS, McNamee KC, Russell G, Goodwin D, Holborow EJ. Fading of immunofluorescence during microscopy: a study of the phenomenon and its remedy. J Immunol Methods. 1982 Dec 17;55(2):231–242. [PubMed]
  • Kaye KM, Izumi KM, Kieff E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9150–9154. [PMC free article] [PubMed]
  • Laherty CD, Hu HM, Opipari AW, Wang F, Dixit VM. The Epstein-Barr virus LMP1 gene product induces A20 zinc finger protein expression by activating nuclear factor kappa B. J Biol Chem. 1992 Dec 5;267(34):24157–24160. [PubMed]
  • Lenardo MJ, Baltimore D. NF-kappa B: a pleiotropic mediator of inducible and tissue-specific gene control. Cell. 1989 Jul 28;58(2):227–229. [PubMed]
  • Liebowitz D, Wang D, Kieff E. Orientation and patching of the latent infection membrane protein encoded by Epstein-Barr virus. J Virol. 1986 Apr;58(1):233–237. [PMC free article] [PubMed]
  • Liu YJ, Joshua DE, Williams GT, Smith CA, Gordon J, MacLennan IC. Mechanism of antigen-driven selection in germinal centres. Nature. 1989 Dec 21;342(6252):929–931. [PubMed]
  • Liu YJ, Mason DY, Johnson GD, Abbot S, Gregory CD, Hardie DL, Gordon J, MacLennan IC. Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis. Eur J Immunol. 1991 Aug;21(8):1905–1910. [PubMed]
  • Lozzio CB, Lozzio BB. Human chronic myelogenous leukemia cell-line with positive Philadelphia chromosome. Blood. 1975 Mar;45(3):321–334. [PubMed]
  • Mann KP, Staunton D, Thorley-Lawson DA. Epstein-Barr virus-encoded protein found in plasma membranes of transformed cells. J Virol. 1985 Sep;55(3):710–720. [PMC free article] [PubMed]
  • Martin J, Sugden B. The latent membrane protein oncoprotein resembles growth factor receptors in the properties of its turnover. Cell Growth Differ. 1991 Dec;2(12):653–600. [PubMed]
  • Martin J, Sugden B. Transformation by the oncogenic latent membrane protein correlates with its rapid turnover, membrane localization, and cytoskeletal association. J Virol. 1991 Jun;65(6):3246–3258. [PMC free article] [PubMed]
  • Martin JM, Veis D, Korsmeyer SJ, Sugden B. Latent membrane protein of Epstein-Barr virus induces cellular phenotypes independently of expression of Bcl-2. J Virol. 1993 Sep;67(9):5269–5278. [PMC free article] [PubMed]
  • Masucci MG, Contreras-Salazar B, Ragnar E, Falk K, Minarovits J, Ernberg I, Klein G. 5-Azacytidine up regulates the expression of Epstein-Barr virus nuclear antigen 2 (EBNA-2) through EBNA-6 and latent membrane protein in the Burkitt's lymphoma line rael. J Virol. 1989 Jul;63(7):3135–3141. [PMC free article] [PubMed]
  • Nuñez G, London L, Hockenbery D, Alexander M, McKearn JP, Korsmeyer SJ. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol. 1990 May 1;144(9):3602–3610. [PubMed]
  • Peng M, Lundgren E. Transient expression of the Epstein-Barr virus LMP1 gene in human primary B cells induces cellular activation and DNA synthesis. Oncogene. 1992 Sep;7(9):1775–1782. [PubMed]
  • Peng M, Lundgren E. Transient expression of the Epstein-Barr virus LMP1 gene in B-cell chronic lymphocytic leukemia cells, T cells, and hematopoietic cell lines: cell-type-independent-induction of CD23, CD21, and ICAM-1. Leukemia. 1993 Jan;7(1):104–112. [PubMed]
  • Perkins ND, Schmid RM, Duckett CS, Leung K, Rice NR, Nabel GJ. Distinct combinations of NF-kappa B subunits determine the specificity of transcriptional activation. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1529–1533. [PMC free article] [PubMed]
  • Pezzella F, Tse AG, Cordell JL, Pulford KA, Gatter KC, Mason DY. Expression of the bcl-2 oncogene protein is not specific for the 14;18 chromosomal translocation. Am J Pathol. 1990 Aug;137(2):225–232. [PMC free article] [PubMed]
  • Rice NR, Ernst MK. In vivo control of NF-kappa B activation by I kappa B alpha. EMBO J. 1993 Dec;12(12):4685–4695. [PMC free article] [PubMed]
  • Rothlein R, Dustin ML, Marlin SD, Springer TA. A human intercellular adhesion molecule (ICAM-1) distinct from LFA-1. J Immunol. 1986 Aug 15;137(4):1270–1274. [PubMed]
  • Rowe M, Evans HS, Young LS, Hennessy K, Kieff E, Rickinson AB. Monoclonal antibodies to the latent membrane protein of Epstein-Barr virus reveal heterogeneity of the protein and inducible expression in virus-transformed cells. J Gen Virol. 1987 Jun;68(Pt 6):1575–1586. [PubMed]
  • Rowe M, Lear AL, Croom-Carter D, Davies AH, Rickinson AB. Three pathways of Epstein-Barr virus gene activation from EBNA1-positive latency in B lymphocytes. J Virol. 1992 Jan;66(1):122–131. [PMC free article] [PubMed]
  • Rowe M, Rooney CM, Edwards CF, Lenoir GM, Rickinson AB. Epstein-Barr virus status and tumour cell phenotype in sporadic Burkitt's lymphoma. Int J Cancer. 1986 Mar 15;37(3):367–373. [PubMed]
  • Rowe M, Rowe DT, Gregory CD, Young LS, Farrell PJ, Rupani H, Rickinson AB. Differences in B cell growth phenotype reflect novel patterns of Epstein-Barr virus latent gene expression in Burkitt's lymphoma cells. EMBO J. 1987 Sep;6(9):2743–2751. [PMC free article] [PubMed]
  • Sanchez-Madrid F, Krensky AM, Ware CF, Robbins E, Strominger JL, Burakoff SJ, Springer TA. Three distinct antigens associated with human T-lymphocyte-mediated cytolysis: LFA-1, LFA-2, and LFA-3. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7489–7493. [PMC free article] [PubMed]
  • Schena M, Larsson LG, Gottardi D, Gaidano G, Carlsson M, Nilsson K, Caligaris-Cappio F. Growth- and differentiation-associated expression of bcl-2 in B-chronic lymphocytic leukemia cells. Blood. 1992 Jun 1;79(11):2981–2989. [PubMed]
  • Tomkinson B, Robertson E, Kieff E. Epstein-Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation. J Virol. 1993 Apr;67(4):2014–2025. [PMC free article] [PubMed]
  • Voraberger G, Schäfer R, Stratowa C. Cloning of the human gene for intercellular adhesion molecule 1 and analysis of its 5'-regulatory region. Induction by cytokines and phorbol ester. J Immunol. 1991 Oct 15;147(8):2777–2786. [PubMed]
  • Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985 Dec;43(3 Pt 2):831–840. [PubMed]
  • Wang D, Liebowitz D, Wang F, Gregory C, Rickinson A, Larson R, Springer T, Kieff E. Epstein-Barr virus latent infection membrane protein alters the human B-lymphocyte phenotype: deletion of the amino terminus abolishes activity. J Virol. 1988 Nov;62(11):4173–4184. [PMC free article] [PubMed]
  • Wang F, Gregory C, Sample C, Rowe M, Liebowitz D, Murray R, Rickinson A, Kieff E. Epstein-Barr virus latent membrane protein (LMP1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP1 cooperatively induce CD23. J Virol. 1990 May;64(5):2309–2318. [PMC free article] [PubMed]
  • Yao QY, Ogan P, Rowe M, Wood M, Rickinson AB. Epstein-Barr virus-infected B cells persist in the circulation of acyclovir-treated virus carriers. Int J Cancer. 1989 Jan 15;43(1):67–71. [PubMed]
  • Young LS, Rowe M. Epstein-Barr virus, lymphomas and Hodgkin's disease. Semin Cancer Biol. 1992 Oct;3(5):273–284. [PubMed]

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