Skip to main content
Download PDF
  • Review
  • Published:

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

Cellular & Molecular Biology Letters volume 14, pages 222–247 (2009)Cite this article

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.

Abbreviations

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. Masucci, M.G. and Ernberg, I. Epstein-Barr virus: adaptation to a life within the immune system. Trends Microbiol. 2 (1994) 125–130.

    Article  PubMed  CAS  Google Scholar 

  2. Junker, A.K. Epstein-Barr virus. Pediatr. Rev. 26 (2005) 79–85.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  17. Thompson, M.P. and Kurzrock, R. Epstein-Barr virus and cancer. Clin. Cancer Res. 10 (2004) 803–821.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Mei-Fong Pang

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

    Kah-Wai Lin

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

    Suat-Cheng Peh

Authors
  1. Mei-Fong Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kah-Wai Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suat-Cheng Peh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suat-Cheng Peh.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pang, MF., Lin, KW. & Peh, SC. The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer. Cell Mol Biol Lett 14, 222–247 (2009). https://doi.org/10.2478/s11658-008-0045-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2478/s11658-008-0045-2

Key words

Cellular & Molecular Biology Letters

ISSN: 1689-1392

Contact us