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Gene Review

BHRF1  -  BHRF1

Human herpesvirus 4

 
 
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Disease relevance of BHRF1

  • Using LCLs transformed with an EBV mutant, in which the BHRF1 gene was deleted, we showed that killing of latently infected cells through the recognition of a protein produced during the lytic cycle is due to transfer of BHRF1 from lytically infected to latently infected cells, which occurs in culture [1].
  • Furthermore, the observation that a potential oncogene activated in human follicular lymphomas is homologous to the BHRF1-encoded polypeptide (M. L. Cleary, S.D. Smith, and J. Sklar, Cell 47:19-28, 1986) suggests a possible role for this putative viral protein in EBV-induced growth transformation of B lymphocytes [2].
  • Part of BHRF1, cloned into a prokaryotic fusion protein expression vector, expressed a fusion protein in Escherichia coli and the purified fusion protein was used to generate a monoclonal antibody against BHRF1 [3].
  • The list of these viral proteins includes BCL-2 homologues (BHRF1 of EBV; KSBCL-2 of KSHV), an inhibitor of apoptosis (IAP) resembling Survivin (KSHV K7), proteins that alter mitochondrial ion permeability and/or membrane potential (HBV HBx, HPV E[wedge]14, HCV p7, and HTLV-1 p13(II)), and K15 of KSHV, a protein with undefined function [4].
  • In addition, a cDNA clone containing BHRF1 from the Burkitt lymphoma cell line Jijoye was also recovered and exhibits a distinctive splicing pattern [5].
 

High impact information on BHRF1

  • Although cytomegalovirus vMIA and Epstein-Barr virus BHRF1 seem to have opposite effects on mitochondrial morphology, they both inhibit cell death [6].
  • Overexpression of KSbcl-2 blocked apoptosis as efficiently as Bcl-2, Bcl-xL, or another viral Bcl-2 homolog encoded by Epstein-Barr virus, BHRF1 [7].
  • We suggest that BHRF1 provides an alternative, Bcl-2-independent, means of enhancing B-cell survival that may operate during the virus lytic cycle [8].
  • In subsequent experiments, stable BHRF1 gene transfectants of Burkitt lymphoma cells paralleled Bcl-2 transfectants in their enhanced survival under conditions that induce cell death by apoptosis [8].
  • The possibility that an analogous effect is operative in lytically infected cells was suggested by the observation of distant sequence homology between an Epstein-Barr virus-coded early lytic cycle protein, BHRF1, and Bcl-2 [8].
 

Chemical compound and disease context of BHRF1

  • Thus, despite several amino acid changes in the BHRF1 ORF of some of the EBV isolates studied, the ability of the protein to protect against cis-platin induced apoptosis is conserved [9].
 

Biological context of BHRF1

 

Anatomical context of BHRF1

  • Long-term MHC class II presentation of the EBV lytic protein BHRF1 by EBV latently infected b cells following capture of BHRF1 antigen [1].
  • We previously reported unexpected killing of EBV-transformed B-lymphoblastoid cells (LCLs) that did not express BHRF1 by CD4+ T cells specific for BHRF1, an EBV lytic cycle protein [1].
  • Moreover, weak BHRF1 signals were found in two T-cell lymphomas where EBER 1/2 expression was detected mainly in sporadic reactive lymphocytes and in one reactive tonsil with sporadic EBER 1/2-positive lymphocytes [10].
  • The BHRF1 product was localized at the periphery of the mitochondria in a pattern similar to that of bcl-2 and by analogy with bcl-2 this is likely to be the functional destination [11].
  • To identify specific proteins from normal epithelial cells that interact with BHRF1 and that might promote or inhibit its anti-apoptotic activity, we screened a yeast two-hybrid cDNA library derived from human normal foreskin keratinocytes and identified a cellular gene encoding human prenylated rab acceptor 1 (hPRA1) [12].
 

Associations of BHRF1 with chemical compounds

 

Physical interactions of BHRF1

 

Other interactions of BHRF1

  • Expression of EA-D, BZLF1, and BHRF1 was increased in response to both, SAH- and 14-3-3 zeta/PLA2 overexpression indicating the initiation of the EBV lytic cycle [18].
  • Two biopsies of oral hairy leukoplakia revealed a sporadic cytoplasmic staining of the BHRF1 and BRLF1 gene products in the basal epithelial layer [19].
  • The use of the Z(S186A) mutant form of ZEBRA, whose transactivation function is manifest only by coexpression of Rta, allows identification of a second class of lytic cycle genes, such as BMRF1 and BHRF1, that are activated in synergy by Rta and ZEBRA [20].
  • We have now found that this second BCL-2 homologue encoded by EBV, BALF1, inhibits the antiapoptotic activity of EBV BHRF1 and of KSBcl-2 in several transfected cell lines [21].
  • Latent BHRF1 transcripts encoding bcl-2 homologue and BCRF1 transcripts encoding viral interleukin (vIL)-10 were detected in one and two of eight patients, respectively [22].
 

Analytical, diagnostic and therapeutic context of BHRF1

References

  1. Long-term MHC class II presentation of the EBV lytic protein BHRF1 by EBV latently infected b cells following capture of BHRF1 antigen. Landais, E., Saulquin, X., Bonneville, M., Houssaint, E. J. Immunol. (2005) [Pubmed]
  2. Isolation and characterization of cDNA clones corresponding to transcripts from the BamHI H and F regions of the Epstein-Barr virus genome. Pfitzner, A.J., Tsai, E.C., Strominger, J.L., Speck, S.H. J. Virol. (1987) [Pubmed]
  3. Identification of an Epstein-Barr virus early gene encoding a second component of the restricted early antigen complex. Pearson, G.R., Luka, J., Petti, L., Sample, J., Birkenbach, M., Braun, D., Kieff, E. Virology (1987) [Pubmed]
  4. Mitochondria as functional targets of proteins coded by human tumor viruses. D'Agostino, D.M., Bernardi, P., Chieco-Bianchi, L., Ciminale, V. Adv. Cancer Res. (2005) [Pubmed]
  5. Complex transcription of the Epstein-Barr virus BamHI fragment H rightward open reading frame 1 (BHRF1) in latently and lytically infected B lymphocytes. Austin, P.J., Flemington, E., Yandava, C.N., Strominger, J.L., Speck, S.H. Proc. Natl. Acad. Sci. U.S.A. (1988) [Pubmed]
  6. Viral modulators of cell death provide new links to old pathways. Irusta, P.M., Chen, Y.B., Hardwick, J.M. Curr. Opin. Cell Biol. (2003) [Pubmed]
  7. A Bcl-2 homolog encoded by Kaposi sarcoma-associated virus, human herpesvirus 8, inhibits apoptosis but does not heterodimerize with Bax or Bak. Cheng, E.H., Nicholas, J., Bellows, D.S., Hayward, G.S., Guo, H.G., Reitz, M.S., Hardwick, J.M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  8. Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. Henderson, S., Huen, D., Rowe, M., Dawson, C., Johnson, G., Rickinson, A. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  9. BHRF1, a viral homologue of the Bcl-2 oncogene, is conserved at both the sequence and functional level in different Epstein-Barr virus isolates. Khanim, F., Dawson, C., Meseda, C.A., Dawson, J., Mackett, M., Young, L.S. J. Gen. Virol. (1997) [Pubmed]
  10. BHRF1, the Epstein-Barr virus (EBV) homologue of the BCL-2 protooncogene, is transcribed in EBV-associated B-cell lymphomas and in reactive lymphocytes. Oudejans, J.J., van den Brule, A.J., Jiwa, N.M., de Bruin, P.C., Ossenkoppele, G.J., van der Valk, P., Walboomers, J.M., Meijer, C.J. Blood (1995) [Pubmed]
  11. Ultrastructural localization of BHRF1: an Epstein-Barr virus gene product which has homology with bcl-2. Hickish, T., Robertson, D., Clarke, P., Hill, M., di Stefano, F., Clarke, C., Cunningham, D. Cancer Res. (1994) [Pubmed]
  12. The cellular protein PRA1 modulates the anti-apoptotic activity of Epstein-Barr virus BHRF1, a homologue of Bcl-2, through direct interaction. Li, L.Y., Shih, H.M., Liu, M.Y., Chen, J.Y. J. Biol. Chem. (2001) [Pubmed]
  13. BHRF1, a viral homologue of the Bcl-2 oncogene, disturbs epithelial cell differentiation. Dawson, C.W., Eliopoulos, A.G., Dawson, J., Young, L.S. Oncogene (1995) [Pubmed]
  14. The ability of BHRF1 to inhibit apoptosis is dependent on stimulus and cell type. Foghsgaard, L., Jäättelä, M. J. Virol. (1997) [Pubmed]
  15. Epstein-Barr virus BHRF1 protein protects intestine 407 epithelial cells from apoptosis induced by tumor necrosis factor alpha and anti-Fas antibody. Kawanishi, M. J. Virol. (1997) [Pubmed]
  16. Epstein-Barr virus BHRF1 protein protects against cell death induced by DNA-damaging agents and heterologous viral infection. Tarodi, B., Subramanian, T., Chinnadurai, G. Virology (1994) [Pubmed]
  17. Epstein-Barr virus (EBV) nuclear antigen leader protein (EBNA-LP) forms complexes with a cellular anti-apoptosis protein Bcl-2 or its EBV counterpart BHRF1 through HS1-associated protein X-1. Matsuda, G., Nakajima, K., Kawaguchi, Y., Yamanashi, Y., Hirai, K. Microbiol. Immunol. (2003) [Pubmed]
  18. Reactivation of the Epstein-Barr virus from viral latency by an S-adenosylhomocysteine hydrolase/14-3-3 zeta/PLA2-dependent pathway. Maas, D., Maret, C., Schaade, L., Scheithauer, S., Ritter, K., Kleines, M. Med. Microbiol. Immunol. (Berl.) (2006) [Pubmed]
  19. Expression of proteins encoded by Epstein-Barr virus trans-activator genes depends on the differentiation of epithelial cells in oral hairy leukoplakia. Becker, J., Leser, U., Marschall, M., Langford, A., Jilg, W., Gelderblom, H., Reichart, P., Wolf, H. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  20. Role of the epstein-barr virus RTA protein in activation of distinct classes of viral lytic cycle genes. Ragoczy, T., Miller, G. J. Virol. (1999) [Pubmed]
  21. Epstein-Barr virus BALF1 is a BCL-2-like antagonist of the herpesvirus antiapoptotic BCL-2 proteins. Bellows, D.S., Howell, M., Pearson, C., Hazlewood, S.A., Hardwick, J.M. J. Virol. (2002) [Pubmed]
  22. The latency pattern of Epstein-Barr virus infection and viral IL-10 expression in cutaneous natural killer/T-cell lymphomas. Xu, Z.G., Iwatsuki, K., Oyama, N., Ohtsuka, M., Satoh, M., Kikuchi, S., Akiba, H., Kaneko, F. Br. J. Cancer (2001) [Pubmed]
 
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