Cellular & Molecular Biology Letters

, Volume 14, Issue 2, pp 222–247 | Cite as

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

Review

Abstract

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.

Key words

Epstein-Barr virus Latent membrane protein Cancer Latency 

Abbreviation

BCR

B-cell receptor

BL

Burkitt’s lymphoma

EBER

EBV-encoded small non-polyadenylated RNA

EBNA

EBV nuclear antigen

EBV

Epstein-Barr virus

ERK

extracellular signal-regulated kinase

GSK-3β

glycogen synthase kinase-3 beta

HL

Hodgkin’s lymphomas

IkBα

inhibitor of NF-κB alpha

IL

interleukin

ITAM

immunoreceptor tyrosine-based activation motif

JNK

c-Jun-N-terminal kinase

LMP

latent membrane protein

MAPK

mitogen-activated protein kinase

NHL

non-Hodgkin’s lymphomas

NK-κB

nuclear factor-kappa B

NPC

nasopharyngeal carcinoma

PI3-K

phosphotidylinositol 3-kinase

PTK

protein tyrosine kinase

STAT

signal transducers and activators of transcription

TGF-β

transforming growth factor-beta

References

  1. 1.
    Masucci, M.G. and Ernberg, I. Epstein-Barr virus: adaptation to a life within the immune system. Trends Microbiol. 2 (1994) 125–130.PubMedCrossRefGoogle Scholar
  2. 2.
    Junker, A.K. Epstein-Barr virus. Pediatr. Rev. 26 (2005) 79–85.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedGoogle Scholar
  8. 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.PubMedGoogle Scholar
  9. 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.PubMedGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 17.
    Thompson, M.P. and Kurzrock, R. Epstein-Barr virus and cancer. Clin. Cancer Res. 10 (2004) 803–821.PubMedCrossRefGoogle Scholar
  18. 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.PubMedCrossRefGoogle Scholar
  19. 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.PubMedGoogle Scholar

Copyright information

© © Versita Warsaw and Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  1. 1.Cancer Center Karolinska, Department of Oncology-PathologyKarolinska InstitutetStockholmSweden
  2. 2.Karolinska Biomics Center, Department of Oncology-PathologyKarolinska InstitutetStockholmSweden
  3. 3.Department of Pathology, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia

Personalised recommendations