Jump to ContentJump to Main Navigation

Cellular and Molecular Biology Letters

Editor-in-Chief: /

4 Issues per year

Impact Factor 2014: 1.593
5-year IMPACT FACTOR: 1.647

SCImago Journal Rank (SJR) 2014: 0.670
Source Normalized Impact per Paper (SNIP) 2014: 0.620
Impact per Publication (IPP) 2014: 1.843


The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer

1Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

2Karolinska Biomics Center, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden

3Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

© 2008 University of Wrocław, Poland. This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License. (CC BY-NC-ND 3.0)

Citation Information: Cellular and Molecular Biology Letters. Volume 14, Issue 2, Pages 222–247, ISSN (Online) 1689-1392, DOI: 10.2478/s11658-008-0045-2, March 2009

Publication History

Published Online:


Epstein-Barr virus (EBV) is a ubiquitous virus with infections commonly resulting in a latency carrier state. Although the exact role of EBV in cancer pathogenesis remains not entirely clear, it is highly probable that it causes several lymphoid and epithelial malignancies, such as Hodgkin’s lymphoma, NK-T cell lymphoma, Burkitt’s lymphoma, and nasopharyngeal carcinoma. EBV-associated malignancies are associated with a latent form of infection, and several of these EBV-encoded latent proteins are known to mediate cellular transformation. These include six nuclear antigens and three latent membrane proteins. Studies have shown that EBV displays distinct patterns of viral latent gene expression in these lymphoid and epithelial tumors. The constant expression of latent membrane protein 2A (LMP2A) at the RNA level in both primary and metastatic tumors suggests that this protein might be a driving factor in the tumorigenesis of EBV-associated malignancies. LMP2A may cooperate with the aberrant host genome, and thereby contribute to malignant transformation by intervening in signaling pathways at multiple points, especially in the cell cycle and apoptotic pathway. This review summarizes the role of EBV-encoded LMP2A in EBV-associated viral latency and cancers. We will focus our discussions on the molecular interactions of each of the conserved motifs in LMP2A, and their involvement in various signaling pathways, namely the B-cell receptor blockade mechanism, the ubiquitin-mediated (Notch and Wnt) pathways, and the MAPK, PI3-K/Akt, NK-κB and STAT pathways, which can provide us with important insights into the roles of LMP2A in the EBV-associated latency state and various malignancies.

Keywords: Epstein-Barr virus; Latent membrane protein; Cancer; Latency

  • [1] Masucci, M.G. and Ernberg, I. Epstein-Barr virus: adaptation to a life within the immune system. Trends Microbiol. 2 (1994) 125–130. http://dx.doi.org/10.1016/0966-842X(94)90599-1 [CrossRef]

  • [2] Junker, A.K. Epstein-Barr virus. Pediatr. Rev. 26 (2005) 79–85. http://dx.doi.org/10.1542/pir.26-3-79 [CrossRef]

  • [3] Schuster, V. and Kreth, H.W. Epstein-Barr virus infection and associated diseases in children. II. Diagnostic and therapeutic strategies. Eur. J. Pediatr. 151 (1992) 794–798. http://dx.doi.org/10.1007/BF01957926 [CrossRef]

  • [4] Schuster, V. and Kreth, H.W. Epstein-Barr virus infection and associated diseases in children. I. Pathogenesis, epidemiology and clinical aspects. Eur. J. Pediatr. 151 (1992) 718–725. http://dx.doi.org/10.1007/BF01959075 [CrossRef]

  • [5] Epstein, M.A., Achong, B.G., Barr, Y.M., Zajac, B., Henle, G. and Henle, W. Morphological and virological investigations on cultured Burkitt tumor lymphoblasts (strain Raji). J. Natl. Cancer Inst. 37 (1966) 547–559.

  • [6] Henle, G., Henle, W. and Diehl, V. Relation of Burkitt’s tumor-associated herpes-ytpe virus to infectious mononucleosis. Proc. Natl. Acad. Sci. USA 59 (1968) 94–101. http://dx.doi.org/10.1073/pnas.59.1.94 [CrossRef]

  • [7] Weiss, L.M., Movahed, L.A., Warnke, R.A. and Sklar, J. Detection of Epstein-Barr viral genomes in Reed-Sternberg cells of Hodgkin’s disease. N. Engl. J. Med. 320 (1989) 502–506.

  • [8] Weiss, L.M., Jaffe, E.S., Liu, X.F., Chen, Y.Y., Shibata, D. and Medeiros, L.J. Detection and localization of Epstein-Barr viral genomes in angioimmunoblastic lymphadenopathy and angioimmunoblastic lymphadenopathy-like lymphoma. Blood 79 (1992) 1789–1795.

  • [9] Jones, J.F., Shurin, S., Abramowsky, C., Tubbs, R.R., Sciotto, C.G., Wahl, R., Sands, J., Gottman, D., Katz, B.Z. and Sklar, J. T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections. N. Engl. J. Med. 318 (1988) 733–741.

  • [10] Gunven, P., Klein, G., Henle, G., Henle, W. and Clifford, P. Epstein-Barr virus in Burkitt’s lymphoma and nasopharyngeal carcinoma. Antibodies to EBV associated membrane and viral capsid antigens in Burkitt lymphoma patients. Nature 228 (1970) 1053–1056. http://dx.doi.org/10.1038/2281053a0 [CrossRef]

  • [11] Bonnet, M., Guinebretiere, J.M., Kremmer, E., Grunewald, V., Benhamou, E., Contesso, G. and Joab, I. Detection of Epstein-Barr virus in invasive breast cancers. J. Natl. Cancer Inst. 91 (1999) 1376–1381. http://dx.doi.org/10.1093/jnci/91.16.1376 [CrossRef]

  • [12] Glaser, S.L., Ambinder, R.F., DiGiuseppe, J.A., Horn-Ross, P.L. and Hsu, J.L. Absence of Epstein-Barr virus EBER-1 transcripts in an epidemiologically diverse group of breast cancers. Int. J. Cancer 75 (1998) 555–558. http://dx.doi.org/10.1002/(SICI)1097-0215(19980209)75:4<555::AID-IJC10>3.0.CO;2-8 [CrossRef]

  • [13] Labrecque, L.G., Barnes, D.M., Fentiman, I.S. and Griffin, B.E. Epstein- Barr virus in epithelial cell tumors: a breast cancer study. Cancer Res. 55 (1995) 39–45.

  • [14] Lespagnard, L., Cochaux, P., Larsimont, D., Degeyter, M., Velu, T. and Heimann, R. Absence of Epstein-Barr virus in medullary carcinoma of the breast as demonstrated by immunophenotyping, in situ hybridization and polymerase chain reaction. Am. J. Clin. Pathol. 103 (1995) 449–452.

  • [15] Niedobitek, G., Herbst, H., Young, L.S., Rowe, M., Dienemann, D., Germer, C. and Stein, H. Epstein-Barr virus and carcinomas. Expression of the viral genome in an undifferentiated gastric carcinoma. Diagn. Mol. Pathol. 1 (1992) 103–108.

  • [16] Oda, K., Tamaru, J., Takenouchi, T., Mikata, A., Nunomura, M., Saitoh, N., Sarashina, H. and Nakajima, N. Association of Epstein-Barr virus with gastric carcinoma with lymphoid stroma. Am. J. Pathol. 143 (1993) 1063–1071.

  • [17] Thompson, M.P. and Kurzrock, R. Epstein-Barr virus and cancer. Clin. Cancer Res. 10 (2004) 803–821. http://dx.doi.org/10.1158/1078-0432.CCR-0670-3 [CrossRef]

  • [18] Clemens, M.J., Laing, K.G., Jeffrey, I.W., Schofield, A., Sharp, T.V., Elia, A., Matys, V., James, M.C. and Tilleray, V.J. Regulation of the interferon-inducible eIF-2 alpha protein kinase by small RNAs. Biochimie 76 (1994) 770–778. http://dx.doi.org/10.1016/0300-9084(94)90081-7 [CrossRef]

  • [19] Brooks, L., Yao, Q.Y., Rickinson, A.B. and Young, L.S. Epstein-Barr virus latent gene transcription in nasopharyngeal carcinoma cells: coexpression of EBNA1, LMP1, and LMP2 transcripts. J. Virol. 66 (1992) 2689–2697.

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

Xiaoyun Lin, Shao Chen, Xiangyang Xue, Lijun Lu, Shanli Zhu, Wenshu Li, Xiangmin Chen, Xiaozhi Zhong, Pengfei Jiang, Torsoo Sophia Sename, Yi Zheng, and Lifang Zhang
Cellular and Molecular Immunology, 2015
Beatrice Ondondo, Lee Faulkner, Neil A. Williams, Andrew J. Morgan, and David J. Morgan
Cancer Medicine, 2015, Volume 4, Number 3, Page 457
Xinjiang Ying, Ruxin Zhang, Hong Wang, and Yaoshu Teng
Gene, 2014, Volume 542, Number 1, Page 77
O. V. Dergai, M. V. Dergai, D. O. Gudkova, L. O. Tsyba, I. Ya. Skrypkina, and A. V. Rynditch
Biopolymers and Cell, 2013, Volume 29, Number 2, Page 131
D Nagel, M Vincendeau, A C Eitelhuber, and D Krappmann
Oncogene, 2014, Volume 33, Number 50, Page 5655
Vasiliki Papadopoulou, Panagiotis T. Diamantopoulos, Elina Kontandreopoulou, Katerina Polonyfi, Eleni Variami, Panagiotis Kouzis, Athanasios Galanopoulos, Nikolaos Spanakis, Konstantinos Zervakis, Theodoros Iliakis, Despoina Perrea, Panagoula Kollia, Theodoros P. Vassilakopoulos, Gerassimos A. Pangalis, Christine Kyrtsonis, George Vaiopoulos, and Nora-Athina Viniou
Leukemia & Lymphoma, 2014, Volume 55, Number 8, Page 1904
B. K. Chung, K. Tsai, L. L. Allan, D. J. Zheng, J. C. Nie, C. M. Biggs, M. R. Hasan, F. K. Kozak, P. van den Elzen, J. J. Priatel, and R. Tan
Blood, 2013, Volume 122, Number 15, Page 2600
Yuan Mao, Da-Wei Zhang, Huijun Zhu, Hong Lin, Lin Xiong, Qing Cao, Ying Liu, Qing-Dong Li, Jia-Ren Xu, Lin-Feng Xu, and Ren-Jie Chen
Diagnostic Pathology, 2012, Volume 7, Number 1, Page 178
Lindsay C. George, Martin Rowe, and Christopher P. Fox
Current Hematologic Malignancy Reports, 2012, Volume 7, Number 4, Page 276
Oleksandr Dergai, Mykola Dergai, Inessa Skrypkina, Liudmila Matskova, Liudmyla Tsyba, Daria Gudkova, and Alla Rynditch
Cellular Signalling, 2013, Volume 25, Number 1, Page 33
Christopher W. Dawson, Rebecca J. Port, and Lawrence S. Young
Seminars in Cancer Biology, 2012, Volume 22, Number 2, Page 144
Wallace B. Morrison
Journal of Veterinary Internal Medicine, 2012, Volume 26, Number 1, Page 18
Xiangyang Xue, Shanli Zhu, Wenshu Li, Jun Chen, Qin Ou, Meixia Zheng, Wenci Gong, and Lifang Zhang
Viral Immunology, 2011, Volume 24, Number 3, Page 227
S. Zhu, X. Xue, J. Liu, L. Lu, P. Zhao, J. Wang, W. Li, and L. Zhang
Acta Biochimica et Biophysica Sinica, 2010, Volume 42, Number 8, Page 515

Comments (0)

Please log in or register to comment.