Antisense oligodeoxynucleotides to latent membrane protein 1 induce growth inhibition, apoptosis and Bcl-2 suppression in Epstein-Barr virus (EBV)-transformed B-lymphoblastoid cells, but not in EBV-positive natural killer cell lymphoma cells
Tadashi Yoshino
Second Department of Pathology, Okayama University Medical School, Okayama, and
Search for more papers by this authorMinoru Takata
Department of Immunology, Kawasaki University Medical School, Kurashiki, Japan
Search for more papers by this authorTadashi Yoshino
Second Department of Pathology, Okayama University Medical School, Okayama, and
Search for more papers by this authorMinoru Takata
Department of Immunology, Kawasaki University Medical School, Kurashiki, Japan
Search for more papers by this authorAbstract
Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) is essential for immortalization of B cells by EBV, protects the infected cells from apoptotic cell death and induces Bcl-2 expression. Suppression of LMP-1 expression by antisense oligodeoxynucleotides (AS-oligo) to LMP-1 inhibits proliferation, promotes apoptosis and suppresses Bcl-2 expression in EBV-transformed B cells. However, the function of LMP-1 expression in EBV-positive natural killer (NK) cell lymphoma cells has not been reported previously. We examined the function of LMP-1 in two EBV-positive NK cell lymphoma cell lines (NK-YS and YT) through suppressing LMP-1 expression by AS-oligo to LMP-1. The AS-oligo to LMP-1 suppressed LMP-1 mRNA and protein expression in two EBV-positive NK cell lymphoma cell lines, as well as in an EBV-transformed B-cell line (CMG-1). Proliferation was inhibited, apoptosis was induced and Bcl-2 expression was suppressed in CMG-1 cells, but none of these events were observed in NK-YS or YT cells. These results suggest that proliferation, inhibition of apoptosis and Bcl-2 expression in EBV-positive NK cell lymphoma cells are not directly regulated by LMP-1 as in EBV-transformed B-cell lines, but are probably mediated through other signal transducing systems.
References
- Baichwal, V.R. & Sugden, B. (1987) Posttranslational processing of an Epstein-Barr virus-encoded membrane protein expressed in cells transformed by Epstein-Barr virus. Journal of Virology, 61, 866–875.
- Berger, C., McQuain, C., Sullivan, J.L., Nadal, D., Quesenberry, P.J., Knecht, H. (1997) The 30-bp deletion variant of Epstein-Barr virus-encoded latent membrane protein-1 prevails in acute infectious mononucleosis. Journal of Infectious Diseases, 176, 1370–1373.
- Brodeur, S.R., Cheng, G., Baltimore, D., Thorley-Lawson, D.A. (1997) Localization of the major NF-kappaB-activating site and the sole TRAF3 binding site of LMP-1 defines two distinct signaling motifs. Journal of Biological Chemistry, 272, 19777–19784.DOI: 10.1074/jbc.272.32.19777
-
Chiang, A.K.,
Tao, Q.,
Srivastava, G.,
Ho, F.C. (1996) Nasal NK- and T-cell lymphomas share the same type of Epstein-Barr virus latency as nasopharyngeal carcinoma and Hodgkin's disease.
International Journal of Cancer, 68, 285–290.DOI: 10.1002/(sici)1097-0215(19961104)68:3<285::aid-ijc3>3.0.co;2-y
10.1002/(sici)1097-0215(19961104)68:3<285::aid-ijc3>3.0.co;2-y CAS PubMed Web of Science® Google Scholar
- Cohen, J.I., Wang, F., Kieff, E. (1991) Epstein-Barr virus nuclear protein 2 mutations define essential domains for transformation and transactivation. Journal of Virology, 65, 2545–2554.
-
Cruz, I.,
Van Den Brule, A.J.,
Brink, A.A.,
Snijders, P.J.,
Walboomers, J.M.,
Van Der Waal, I.,
Meijer, C.J. (2000) No direct role for Epstein-Barr virus in oral carcinogenesis: a study at the DNA, RNA and protein levels.
International Journal of Cancer, 86, 356–361.DOI: 10.1002/(sici)1097-0215(20000501)86:3<356::aid-ijc9>3.3.co;2-n
10.1002/(SICI)1097-0215(20000501)86:3<356::AID-IJC9>3.0.CO;2-W CAS PubMed Web of Science® Google Scholar
- Devergne, O., Hatzivassiliou, E., Izumi, K.M., Kaye, K.M., Kleijen, M.F., Kieff, E., Mosialos, G. (1996) Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP-1 domain important for B-lymphocyte transformation: role in NF-κB activation. Molecular and Cellular Biology, 16, 7098–7108.
- Dirnhofer, S., Angeles-Angeles, A., Ortiz-Hidalgo, C., Reyes, E., Gredler, E., Krugmann, J., Fend, F., Quintanilla-Martinez, L. (1999) High prevalence of a 30-base pair deletion in the Epstein-Barr virus (EBV) latent membrane protein 1 gene and of strain type B EBV in Mexican classical Hodgkin's disease and reactive lymphoid tissue. Human Pathology, 30, 781–787.
- Dolcetti, R., Zancai, P., De Re, V., Gloghini, A., Bigoni, B., Pivetta, B., De Vita, S., Carbone, A., Boiocchi, M. (1997) Epstein-Barr virus strains with latent membrane protein-1 deletions: prevalence in the Italian population and high association with human immunodeficiency virus-related Hodgkin's disease. Blood, 89, 1723–1731.
- Eliopoulos, A.G. & Rickinson, A.B. (1998) Epstein-Barr virus: LMP-1 masquerades as an active receptor. Current Biology, 8, 196–198.
- Eliopoulos, A.G., Blake, S.M., Floettmann, J.E., Rowe, M., Young, L.S. (1999) Epstein-Barr virus encoded latent membrane protein 1 activates the JNK pathway through its extreme C terminus via a mechanism involving TRADD and TRAF2. Journal of Virology, 73, 1023–1035.
- Fennewald, S., Van Santen, V., Kieff, E. (1984) Nucleotide sequence of an mRNA transcribed in latent growth-transforming virus infection indicates that it may encode a membrane protein. Journal of Virology, 51, 411–419.
- Gires, O., Zimber-Strobl, U., Gonnella, R., Ueffing, M., Marschall, G., Zeidler, R., Pich, D., Hammerschmidt, W. (1997) Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO Journal, 16, 6131–6140.
- Gires, O., Kohlhuber, F., Kilger, E., Baumann, M., Kieser, A., KaiSeries, C., Zeidler, R., Scheffer, B., Ueffing, M., Hammerschmidt, W. (1999) Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins. EMBO Journal, 18, 3064–3073.
- Hamilton-Dutoit, S.J., Rea, D., Raphael, M., Sandjev, K., Delecluse, H.J., Gisselbrecht, C., Marelle, L., Van Krieken, H.J., Pallesen, G. (1993) Epstein-Barr virus-latent gene expression and tumor cell phenotype in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Correlation of lymphoma phenotype with three distinct patterns of viral latency. American Journal of Pathology, 143, 1072–1085.
- Hammerschmidt, W. & Sugden, B. (1989) Genetic analysis of immortalizing functions of Epstein-Barr virus in human B lymphocytes. Nature, 340, 393–397.
- Henderson, S., Rowe, M., Gregory, C., Croom-Carter, D., Wang, F., Longnecker, R., Kieff, E., Rickinson, A. (1991) Induction of bcl-2 expression by Epstein-Barr virus latent membrane protein 1 protects infected B cells from programmed cell death. Cell, 65, 1107–1115.
- Hennessy, K., Fennewald, S., Hummel, M., Cole, T., Kieff, E. (1984) A membrane protein encoded by Epstein-Barr virus in latent growth-transforming infection. Proceedings of the National Academy of Sciences of the United States of America, 81, 7207–7211.
- Jiang, S., Munker, R., Andreeff, M. (1996) Bcl-2 is expressed in human natural killer cells and is regulated by interleukin-2. Natural Immunity, 15, 312–317.
- Kaye, K.M., Izumi, K.M., Kieff, E. (1993) Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proceedings of the National Academy of Sciences of the United States of America, 90, 9150–9154.
- Kaye, K.M., Devergne, O., Harada, J.N., Izumi, K.M., Yalamanchili, R., Kieff, E., Mosialos, G. (1996) Tumor necrosis factor receptor associated factor 2 is a mediator of NF-κB activation by latent infection membrane protein 1, the Epstein-Barr virus transforming protein. Proceedings of the National Academy of Sciences of the United States of America, 93, 11085–11090.
- Kenney, J.L., Guinness, M.E., Curiel, T., Lacy, J. (1998) Antisense to the Epstein-Barr Virus (EBV)-encoded latent membrane protein 1 (LMP-1) suppresses LMP-1 and bcl-2 expression and promotes apoptosis in EBV-immortalized B cells. Blood, 92, 1721–1727.
- Kieff, E. (1996) Epstein-Barr virus and its replication. In: Fields Virology (ed. by B.N. Fields, D.M. Knipe & P.M. Howley), pp. 2343–2396. Lippincott-Raven, Philadelphia.
- Kieff, E. & Liebowitz, D. (1990) Epstein-Barr virus and its replication. In: Virology (ed. by B.N. Fields, D.M. Knipe & R.M. Chanock), p. 1889. Raven, New York, NY.
- Kieser, A., Kilger, E., Gires, O., Ueffing, M., Kolch, W., Hammerschmidt, W. (1997) Epstein-Barr virus latent membrane protein-1 triggers AP-1 activity via the C-Jun N-terminal kinase cascade. EMBO Journal, 16, 6478–6485.
- Kilger, E., Kieser, A., Baumann, M., Hammerschmidt, W. (1998) Epstein-Barr virus mediated B-cell proliferation is dependent upon latent membrane protein 1, which stimulates an activated CD40 receptor. EMBO Journal, 17, 1700–1709.
- Kingma, D.W., Weiss, W.B., Jaffe, E.S., Kumar, S., Frekko, K., Raffeld, M. (1996) Epstein-Barr virus latent membrane protein-1 oncogene deletions: correlations with malignancy in Epstein-Barr virus-associated lymphoproliferative disorders and malignant lymphomas. Blood, 88, 242–251.
- Liang, R., Todd, D., Chan, T.K., Chiu, E., Lie, A., Kwong, Y.L., Choy, D., Ho, F.C. (1995) Treatment outcome and prognostic factor for primary nasal lymphoma. Journal of Clinical Oncology, 13, 666–670.
- Liebowitz, D. (1994) Nasopharyngeal carcinoma: The Epstein–Barr virus association. Seminars in Oncology, 21, 376–381.
- Liebowitz, D., Wang, D., Kieff, E. (1986) Orientation and patching of the latent infection membrane protein encoded by Epstein-Barr virus. Journal of Virology, 58, 233–237.
- Mansoor, A., Stevenson, M.S., Li, R.Z., Frekko, K., Weiss, W., Ahmad, M., Khan, A.H., Mushtaq, S., Saleem, M., Raffeld, M., Kingma, D.W., Jaffe, E.S. (1997) Prevalence of Epstein-Barr viral sequences and EBV LMP-1 oncogene deletions in Burkitt's lymphoma from Pakistan: epidemiological correlations. Human Pathology, 28, 283–288.
- Middleton, T., Gahn, T.A., Martin, J.M., Sugden, B. (1991) Immortalizing genes of Epstein-Barr virus. In: Advances in Viral Research, (ed. by K. Maramorosch, F.A. Murphy & J.A. Shatkin), pp. 19–55. Academic, San Diego, CA.
- Miller, C.L., Burkhardt, A.L., Lee, J.H., Stealey, B., Longnecker, R., Bolen, J.B., Kieff, E. (1995) Integral membrane protein 2 of Epstein-Barr virus regulates reactivation from latency through dominant negative effects on protein-tyrosine kinases. Immunity, 2, 155–166.
- Miller, W.E., Mosialos, G., Kieff, E., Raab-Traub, N. (1997) Epstein-Barr virus LMP-1 induction of the epidermal growth factor receptor is mediated through a TRAF signaling pathway distinct from NF-κB activation. Journal of Virology, 71, 586–594.
- Mosialos, G., Birkenbach, M., Yalamanchili, R., VanArsdale, T., Ware, C., Kieff, E. (1995) The Epstein-Barr virus transforming protein LMP-1 engages signaling proteins for the tumor necrosis factor receptor family. Cell, 80, 389–399.
- Murray, P.G., Swinnen, L.J., Constandinou, C.M., Pyle, J.M., Carr, T.J., Hardwick, J.M., Ambinder, R.F. (1996) Bcl-2 but not its Epstein-Barr virus-encoded homologue, BHRF-1, is commonly expressed in posttransplantation lymphoproliferative disorders. Blood, 87, 706–711.
- Okan, I., Wang, Y., Chen, F., Hu, L.F., Imreh, S., Klein, G., Wiman, G. (1995) The EBV-encoded LMP-1 protein inhibits p53-triggered apoptosis but not growth arrest. Oncogene, 11, 1027–1031.
- Rickinson, A.B. & Kieff, E. (1996) Epstein-Barr virus. In: Fields Virology (ed. by B.N. Fields, D.M. Knipe & P.M. Howley), pp. 2397–2446. Lippincott-Raven, Philadelphia.
- Rowe, M., Peng-Pilon, M., Huen, D.S., Hardy, R., Croom-Carter, D., Lundgren, E., Rickinson, A.B. (1994) Upregulation of bcl-2 by the Epstein-Barr virus latent-membrane protein LMP-1: a B-cell-specific response that is delayed relative to NF-κB activation and to induction of cell surface markers. Journal of Virology, 68, 5602–5612.
- Sandberg, M., Hammerschmidt, W., Sugden, B. (1997) Characterization of LMP−1′S association with TRAF1, TRAF2, and TRAF3. Journal of Virology, 71, 4649–4656.
- Speck, S.H. & Strominger, J.L. (1989) Transcription of Epstein-Barr virus in latently infected, growth transformed lymphocytes. In: Advances in Viral Oncology, (ed. by G. Klein), pp. 133–163. Raven, New York, NY.
- Suzumiya, J., Ohshima, K., Takeshita, M., Kanda, M., Kawasaki, C., Kimura, N., Tamura, K., Kikuchi, M. (1999) Nasal lymphomas in Japan: a high prevalence of Epstein-Barr virus type A and deletion within the latent membrane protein gene. Leukemia and Lymphoma, 35, 567–578.
- Tomkinson, B., Robertson, E., Kieff, E. (1993) Epstein-Barr virus nuclear proteins EBNA-3A, and EBNA-3C are essential for B-lymphocyte growth tranformation. Journal of Virology, 67, 2014–2025.
- Tsuchiyama, J., Yoshino, T., Mori, M., Kondoh, E., Oka, T., Akagi, T., Hiraki, A., Nakayama, H., Shibuya, A., Ma, Y., Kawabata, T., Okada, S., Harada, M. (1998) Characterization of a novel human natural killer-cell line (NK-YS) established from natural killer cell lymphoma/leukemia associated with Epstein-Barr Virus infection. Blood, 92, 1374–1383.
- Wang, F., Gregory, C., Sample, C., Rowe, M., Liebowitz, D., Murray, R., Rickinson, A., Kieff, E. (1990) Epstein-Barr virus latent-membrane protein (LMP-1) and nuclear proteins 2 and 3C are effectors of phenotypic changes in B lymphocytes: EBNA-2 and LMP-1 cooperatively induce CD23. Journal of Virology, 64, 2309–2318.
- Yoneda, N., Tatsumi, E., Kawano, S., Teshigawara, K., Oka, T., Fukuda, M., Yamaguchi, N. (1992) Detection of Epstein-Barr virus genome in natural-killer-like cell line, YT. Leukemia, 6, 136–141.