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Gene Review

BYRF1  -  EBNA-2 nuclear protein

Human herpesvirus 4

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Disease relevance of EBNA-2

  • Two Epstein-Barr virus (EBV) types are known, EBV1 and EBV2, which possess substantially diverged alleles for latency genes EBNA-2, EBNA-3A, EBNA-3B and EBNA-3C but are thought to be otherwise similar [1].
  • MAIN OUTCOME MEASURES: Antibodies including IgA against EBV viral capsid antigen (VCA) and IgG against VCA, nuclear antigens (EBNA complex, EBNA-1, and EBNA-2), diffuse and restricted early antigens, and cytomegalovirus [2].
  • In the present investigation we show that the resistance to the anti-proliferative effect of IFN class I on certain EBV-carrying Burkitt lymphoma cell lines is connected to the presence of the EBNA-2 gene and parts of the EBNA-5 gene of the EBV genome [3].
  • The demonstration of multiple variably sized BamHI H fragments on Southern blot analysis and cloning of the EBNA-2 gene coding region also suggested the presence of multiple viral strains or variants coinfecting hairy leukoplakia [4].
  • To determine whether another transcriptional activator can substitute for this function, a chimeric virus was constructed that contained a portion of the transcriptional activation domain from the herpes simplex virus VP16 protein inserted in place of the 14-amino acid domain of EBNA-2 [5].

High impact information on EBNA-2

  • Epstein-Barr virus-associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2 [6].
  • Here we identify a subset of BL tumors in which the Latency III-associated EBNA promoter Wp is active and most EBNAs are expressed, but where a gene deletion has specifically abrogated the expression of EBNA2 [6].
  • The malignant cells latently infected with EBV typically express the transcription factor EBNA2 as one of nine latent viral genes [7].
  • We tested whether an EBNA2-responsive EBV promoter may selectively target EBV-related lymphoma cells by virus-regulated expression of a suicide gene [7].
  • Using the BamC promoter driving a hygromycin-thymidine kinase fusion gene or controls, we demonstrated that sensitivity to ganciclovir was selectively enhanced in cells expressing EBNA2 [7].

Chemical compound and disease context of EBNA-2


Biological context of EBNA-2


Anatomical context of EBNA-2

  • This cell line allowed us to examine expression from the endogenous latency gene promoters in the context of an actual latent infection and the presence of other EBNA proteins, in particular EBNA-2, which is presumed to coregulate transcription with EBNA-3C [16].
  • We also show that c-MYC, as well as EBNA2, can stimulate CTCF mRNA levels, suggesting that CTCF levels may contribute to B-cell differentiation as well as EBV latency type determination [13].
  • Thus, EBNA-2 is an essential molecule in lymphocyte growth transformation by EBV and a major determinant of the differences between EBV-1 and EBV-2 in lymphocyte growth transformation [17].
  • Lack of the expression of EBNA-2 and LMP-1 in T-cell neoplasms possessing Epstein-Barr virus [18].
  • Group 2 isolates (HD, n = 1; AILD, n = B-NHL, n = 1; tonsils of EBV-seropositive children, n = 9; IM, n = 20 showed a nucleotide change at position 49095 in the EBNA-2 gene, leading to an amino acid substitution (Pro-->Ser), and EBV type-2 sequences in the EBER region [19].

Associations of EBNA-2 with chemical compounds


Enzymatic interactions of EBNA-2


Regulatory relationships of EBNA-2


Other interactions of EBNA-2


Analytical, diagnostic and therapeutic context of EBNA-2

  • The primers designed to amplify these three gene loci encompass either type-specific deletion sequences (EBNA-2 and EBNA-3C) or type-specific point mutations (EBER) that identify the virus strain based on the sizes of the polymerase chain reaction (PCR)-amplified products or the mobility shifts in single-strand conformation polymorphism analysis [36].
  • Western blot analysis for existence of size polymorphisms in three classes of Epstein-Barr nuclear antigens (EBNA-1, EBNA-2, and EBNA-3) confirmed the DNA results [37].
  • EBNA-2-positive cells were detected by anti-complement immunofluorescence staining just 12 h after addition of 4 microM 5-AzaC and reached a maximum number at 72 h, when up to 75% of the population was positive [38].
  • We have shown by both gel filtration and sucrose gradient analysis that the purified material corresponds to a multimer containing eight EBNA-2 subunits [39].
  • Although EBNA-2 and EBNA-3C are extensively associated with RBPJkappa, a fraction of RBPJkappa appears to be free of EBNAs after repeated immunoprecipitations with anti-EBNA, Epstein-Barr virus-immune, human antibody [40].


  1. The genome of Epstein-Barr virus type 2 strain AG876. Dolan, A., Addison, C., Gatherer, D., Davison, A.J., McGeoch, D.J. Virology (2006) [Pubmed]
  2. Multiple sclerosis and Epstein-Barr virus. Levin, L.I., Munger, K.L., Rubertone, M.V., Peck, C.A., Lennette, E.T., Spiegelman, D., Ascherio, A. JAMA (2003) [Pubmed]
  3. An Epstein-Barr virus immortalization associated gene segment interferes specifically with the IFN-induced anti-proliferative response in human B-lymphoid cell lines. Aman, P., von Gabain, A. EMBO J. (1990) [Pubmed]
  4. Coinfection with multiple strains of the Epstein-Barr virus in human immunodeficiency virus-associated hairy leukoplakia. Walling, D.M., Edmiston, S.N., Sixbey, J.W., Abdel-Hamid, M., Resnick, L., Raab-Traub, N. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  5. A region of herpes simplex virus VP16 can substitute for a transforming domain of Epstein-Barr virus nuclear protein 2. Cohen, J.I. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  6. Epstein-Barr virus-associated Burkitt lymphomagenesis selects for downregulation of the nuclear antigen EBNA2. Kelly, G., Bell, A., Rickinson, A. Nat. Med. (2002) [Pubmed]
  7. Epstein-Barr virus-driven gene therapy for EBV-related lymphomas. Franken, M., Estabrooks, A., Cavacini, L., Sherburne, B., Wang, F., Scadden, D.T. Nat. Med. (1996) [Pubmed]
  8. Zebularine reactivates silenced E-cadherin but unlike 5-Azacytidine does not induce switching from latent to lytic Epstein-Barr virus infection in Burkitt's lymphoma Akata cells. Rao, S.P., Rechsteiner, M.P., Berger, C., Sigrist, J.A., Nadal, D., Bernasconi, M. Mol. Cancer (2007) [Pubmed]
  9. A selectable marker allows investigation of a nontransforming Epstein-Barr virus mutant. Marchini, A., Cohen, J.I., Wang, F., Kieff, E. J. Virol. (1992) [Pubmed]
  10. Complete genomic sequence of an Epstein-Barr virus-related herpesvirus naturally infecting a new world primate: a defining point in the evolution of oncogenic lymphocryptoviruses. Rivailler, P., Cho, Y.G., Wang, F. J. Virol. (2002) [Pubmed]
  11. Epstein-Barr virus nuclear antigen 3C putative repression domain mediates coactivation of the LMP1 promoter with EBNA-2. Lin, J., Johannsen, E., Robertson, E., Kieff, E. J. Virol. (2002) [Pubmed]
  12. Epstein-Barr virus nuclear antigen 2 is a transcriptional suppressor of the immunoglobulin mu gene: implications for the expression of the translocated c-myc gene in Burkitt's lymphoma cells. Jochner, N., Eick, D., Zimber-Strobl, U., Pawlita, M., Bornkamm, G.W., Kempkes, B. EMBO J. (1996) [Pubmed]
  13. Regulation of Epstein-Barr virus latency type by the chromatin boundary factor CTCF. Chau, C.M., Zhang, X.Y., McMahon, S.B., Lieberman, P.M. J. Virol. (2006) [Pubmed]
  14. Identification of rare Epstein-Barr virus infected memory B cells and plasma cells in non-monomorphic post-transplant lymphoproliferative disorders and the signature of viral signaling. Shaknovich, R., Basso, K., Bhagat, G., Mansukhani, M., Hatzivassiliou, G., Murty, V.V., Buettner, M., Niedobitek, G., Alobeid, B., Cattoretti, G. Haematologica (2006) [Pubmed]
  15. Epstein-Barr virus nuclear antigen 2 exerts its transactivating function through interaction with recombination signal binding protein RBP-J kappa, the homologue of Drosophila Suppressor of Hairless. Zimber-Strobl, U., Strobl, L.J., Meitinger, C., Hinrichs, R., Sakai, T., Furukawa, T., Honjo, T., Bornkamm, G.W. EMBO J. (1994) [Pubmed]
  16. Epstein-Barr Virus EBNA-3C Is Targeted to and Regulates Expression from the Bidirectional LMP-1/2B Promoter. Jim??nez-Ram??rez, C., Brooks, A.J., Forshell, L.P., Yakimchuk, K., Zhao, B., Fulgham, T.Z., Sample, C.E. J. Virol. (2006) [Pubmed]
  17. Epstein-Barr virus nuclear protein 2 is a key determinant of lymphocyte transformation. Cohen, J.I., Wang, F., Mannick, J., Kieff, E. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  18. Lack of the expression of EBNA-2 and LMP-1 in T-cell neoplasms possessing Epstein-Barr virus. Suzushima, H., Asou, N., Fujimoto, T., Nishimura, S., Okubo, T., Yamasaki, H., Osato, M., Matsuoka, M., Tsukamoto, A., Takai, K. Blood (1995) [Pubmed]
  19. Common Epstein-Barr virus (EBV) type-1 variant strains in both malignant and benign EBV-associated disorders. Schuster, V., Ott, G., Seidenspinner, S., Kreth, H.W. Blood (1996) [Pubmed]
  20. The Epstein-Barr virus immortalizing protein EBNA-2 is targeted to DNA by a cellular enhancer-binding protein. Ling, P.D., Rawlins, D.R., Hayward, S.D. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  21. The Epstein-Barr virus nuclear antigen 2 transactivator is directed to response elements by the J kappa recombination signal binding protein. Grossman, S.R., Johannsen, E., Tong, X., Yalamanchili, R., Kieff, E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  22. The Epstein-Barr virus EBNA-2 gene in oral hairy leukoplakia: strain variation, genetic recombination, and transcriptional expression. Walling, D.M., Perkins, A.G., Webster-Cyriaque, J., Resnick, L., Raab-Traub, N. J. Virol. (1994) [Pubmed]
  23. Identification of major phosphorylation sites of Epstein-Barr virus nuclear antigen leader protein (EBNA-LP): ability of EBNA-LP to induce latent membrane protein 1 cooperatively with EBNA-2 is regulated by phosphorylation. Yokoyama, A., Tanaka, M., Matsuda, G., Kato, K., Kanamori, M., Kawasaki, H., Hirano, H., Kitabayashi, I., Ohki, M., Hirai, K., Kawaguchi, Y. J. Virol. (2001) [Pubmed]
  24. Epstein-Barr virus nuclear protein 2 mutations define essential domains for transformation and transactivation. Cohen, J.I., Wang, F., Kieff, E. J. Virol. (1991) [Pubmed]
  25. Epstein-Barr viral DNA in acute large granular lymphocyte (natural killer) leukemic cells. Hart, D.N., Baker, B.W., Inglis, M.J., Nimmo, J.C., Starling, G.C., Deacon, E., Rowe, M., Beard, M.E. Blood (1992) [Pubmed]
  26. Epstein-Barr virus nuclear protein 2 transactivation of the latent membrane protein 1 promoter is mediated by J kappa and PU.1. Johannsen, E., Koh, E., Mosialos, G., Tong, X., Kieff, E., Grossman, S.R. J. Virol. (1995) [Pubmed]
  27. Epstein-Barr virus nuclear protein LP stimulates EBNA-2 acidic domain-mediated transcriptional activation. Harada, S., Kieff, E. J. Virol. (1997) [Pubmed]
  28. Epstein-Barr virus infection in sarcomatoid renal cell carcinoma tissues. Kim, K.H., Han, E.M., Lee, E.S., Park, H.S., Kim, I., Kim, Y.S. BJU international. (2005) [Pubmed]
  29. Epstein-Barr virus EBNA3A and EBNA3C proteins both repress RBP-J kappa-EBNA2-activated transcription by inhibiting the binding of RBP-J kappa to DNA. Waltzer, L., Perricaudet, M., Sergeant, A., Manet, E. J. Virol. (1996) [Pubmed]
  30. EBNA2 interferes with the germinal center phenotype by downregulating BCL6 and TCL1 in non-Hodgkin's lymphoma cells. Boccellato, F., Anastasiadou, E., Rosato, P., Kempkes, B., Frati, L., Faggioni, A., Trivedi, P. J. Virol. (2007) [Pubmed]
  31. Multiplex-nested RT-PCR to evaluate latent and lytic Epstein Barr virus gene expression. Bergallo, M., Costa, C., Baro, S., Musso, T., Balbo, L., Merlino, C., Cavallo, R. J. Biotechnol. (2007) [Pubmed]
  32. Structure and coding content of CST (BART) family RNAs of Epstein-Barr virus. Smith, P.R., de Jesus, O., Turner, D., Hollyoake, M., Karstegl, C.E., Griffin, B.E., Karran, L., Wang, Y., Hayward, S.D., Farrell, P.J. J. Virol. (2000) [Pubmed]
  33. EBNA-2 and EBNA-LP cooperate to cause G0 to G1 transition during immortalization of resting human B lymphocytes by Epstein-Barr virus. Sinclair, A.J., Palmero, I., Peters, G., Farrell, P.J. EMBO J. (1994) [Pubmed]
  34. Epstein-Barr virus (EBV) recombinants: use of positive selection markers to rescue mutants in EBV-negative B-lymphoma cells. Wang, F., Marchini, A., Kieff, E. J. Virol. (1991) [Pubmed]
  35. Down-regulation of Epstein-Barr virus nuclear antigen 1 in Reed-Sternberg cells of Hodgkin's disease. Khan, G., Naase, M.A. J. Clin. Pathol. (1995) [Pubmed]
  36. Precision of genotyping of Epstein-Barr virus by polymerase chain reaction using three gene loci (EBNA-2, EBNA-3C, and EBER): predominance of type A virus associated with Hodgkin's disease. Lin, J.C., Lin, S.C., De, B.K., Chan, W.P., Evatt, B.L., Chan, W.C. Blood (1993) [Pubmed]
  37. Epstein-Barr virus transmission from a blood donor to an organ transplant recipient with recovery of the same virus strain from the recipient's blood and oropharynx. Alfieri, C., Tanner, J., Carpentier, L., Perpête, C., Savoie, A., Paradis, K., Delage, G., Joncas, J. Blood (1996) [Pubmed]
  38. 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. Masucci, M.G., Contreras-Salazar, B., Ragnar, E., Falk, K., Minarovits, J., Ernberg, I., Klein, G. J. Virol. (1989) [Pubmed]
  39. Epstein-Barr virus nuclear protein 2A forms oligomers in vitro and in vivo through a region required for B-cell transformation. Tsui, S., Schubach, W.H. J. Virol. (1994) [Pubmed]
  40. EBNA-2 and EBNA-3C extensively and mutually exclusively associate with RBPJkappa in Epstein-Barr virus-transformed B lymphocytes. Johannsen, E., Miller, C.L., Grossman, S.R., Kieff, E. J. Virol. (1996) [Pubmed]
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