Full Text:   <2708>

CLC number: R373.9

On-line Access: 2013-01-08

Received: 2012-07-09

Revision Accepted: 2012-11-23

Crosschecked: 2012-11-29

Cited: 12

Clicked: 5607

Citations:  Bibtex RefMan EndNote GB/T7714

-   Go to

Article info.
1. Reference List
Open peer comments

Journal of Zhejiang University SCIENCE B 2013 Vol.14 No.1 P.8-24


Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

Author(s):  Qin Fu, Chen He, Zheng-rong Mao

Affiliation(s):  Department of Pathology and Pathophysiology, School of Medicine, Zhejiang University, Hangzhou 310058, China

Corresponding email(s):   maozr@zju.edu.cn

Key Words:  Epstein-Barr virus, Bcl family members, Apoptosis, Drugs therapy

Qin Fu, Chen He, Zheng-rong Mao. Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells[J]. Journal of Zhejiang University Science B, 2013, 14(1): 8-24.

@article{title="Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells",
author="Qin Fu, Chen He, Zheng-rong Mao",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells
%A Qin Fu
%A Chen He
%A Zheng-rong Mao
%J Journal of Zhejiang University SCIENCE B
%V 14
%N 1
%P 8-24
%@ 1673-1581
%D 2013
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1200189

T1 - Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells
A1 - Qin Fu
A1 - Chen He
A1 - Zheng-rong Mao
J0 - Journal of Zhejiang University Science B
VL - 14
IS - 1
SP - 8
EP - 24
%@ 1673-1581
Y1 - 2013
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1200189

epstein-Barr virus (EBV), a human gammaherpesvirus carried by more than 90% of the world’s population, is associated with malignant tumors such as Burkitt’s lymphoma (BL), Hodgkin lymphoma, post-transplant lymphoma, extra-nodal natural killer/T cell lymphoma, and nasopharyngeal and gastric carcinomas in immune-compromised patients. In the process of infection, EBV faces challenges: the host cell environment is harsh, and the survival and apoptosis of host cells are precisely regulated. Only when host cells receive sufficient survival signals may they immortalize. To establish efficiently a lytic or long-term latent infection, EBV must escape the host cell immunologic mechanism and resist host cell apoptosis by interfering with multiple signaling pathways. This review details the apoptotic pathway disrupted by EBV in EBV-infected cells and describes the interactions of EBV gene products with host cellular factors as well as the function of these factors, which decide the fate of the host cell. The relationships between other EBV-encoded genes and proteins of the B-cell leukemia/lymphoma (Bcl) family are unknown. Still, EBV seems to contribute to establishing its own latency and the formation of tumors by modifying events that impact cell survival and proliferation as well as the immune response of the infected host. We discuss potential therapeutic drugs to provide a foundation for further studies of tumor pathogenesis aimed at exploiting novel therapeutic strategies for EBV-associated diseases.

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Abdulkarim, B., Sabri, S., Zelenika, D., Deutsch, E., Frascogna, V., Klijanienko, J., Vainchenker, W., Joab, I., Bourhis, J., 2003. Antiviral agent Cidofovir decreases Epstein-Barr virus (EBV) oncoproteins and enhances the radiosensitivity in EBV-related malignancies. Oncogene, 22(15):2260-2271.

[2]Altmann, M., Pich, D., Ruiss, R., Hammers Chmidt, W., Wang, J., Sugden, B., 2006. Transcriptional activation by EBV nuclear antigen 1 is essential for the expression of EBV’s transforming genes. PNAS, 103(38):14188-14193.

[3]Anderton, E., Yee, J., Smith, P., Crook, T., White, R.E., 2008. Two Epstein-Barr virus (EBV) oncoproteins cooperate to repress expression of the proapoptotic tumor-suppressor Bim: clues to the pathogenesis of Burkitt’s lymphoma. Oncogene, 27(4):421-433.

[4]Artavanis-Tsakonas, S., Matsuno, K., Fortini, M.E., 1995. Notch signaling. Science, 268(5208):225-232.

[5]Azmi, A.S., Mohammad, R.M., 2009. Non-peptidic small molecule inhibitors against Bcl-2 for cancer therapy. J. Cell. Physiol., 218(1):13-21.

[6]Babcock, G.J., Hochberg, D., Thorley-Lawson, D.A., 2000. The expression pattern of Epstein-Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity, 13(4):497-506.

[7]Bakhshi, A., Jensen, J.P., Goldman, P., Wright, J.J., McBride, O.W., Epstein, A.L., Korsmeyer, S.J., 1985. Cloning the chromosomal breakpoint of the (14; 18) human lymphomas: clustering around JH on chromosome 14 and near atranscriptional unit on 18. Cell, 41(3):899-906.

[8]Baldwin, A.S.Jr., 2001. Series introduction: the transcription factor NF-κB and human disease. J. Clin. Invest., 107(1):3-6.

[9]Bartholomeusz, G., Wu, Y., Ali Seyed, M., Xia, W., Kwong, K.Y., Hortobagyi, G., Hung, M.C., 2006. Nuclear translocation of the pro-apoptotic Bcl-2 family member bok induces apoptosis. Mol. Carcinogen., 45(2):73-83.

[10]Bellows, D.S., Howell, M., Pearson, C., Hazlewood, S.A., Hardwick, J.M., 2002. Epstein-Barr virus BALF1 is a BCL-2-like antagonist of the herpesvirus antiapoptotic BCL-2 proteins. J. Virol., 76(5):2469-2479.

[11]Bieging, K.T., Amick, A.C., Longnecker, R., 2009. Epstein-Barr virus LMP2A bypasses p53 inactivation in a MYC model of lymphoma genesis. PNAS, 106(42):17945-17950.

[12]Bieging, K.T., Swanson-Mungerson, M., Amick, A.C., Longnecker, R., 2010. Epstein-Barr virus in Burkitt’s lymphoma: a role for latent membrane protein 2A. Cell Cycle, 9(5):901-908.

[13]Bornkamm, G.W., Hammerschmidt, W., 2001. Molecular virology of Epstein-Barr virus. Philosoph. Transact. Roy. Soc. B, 356(1408):437-459.

[14]Boyd, J.M., Gallo, G.J., Elanqovan, B., Houqhton, B., Malstrom, S., Avery, B.J., Ebb, R.G., Subramanian, T., Chittenden, T., Lutz, R.J., 1995. Bik, a novel death-inducing protein shares a distinct sequence motif with Bcl-2 family proteins and interacts with viral and cellular survival-promoting proteins. Oncogene, 11(9):1921-1928.

[15]Cai, X., Schafer, A., Lu, S., Bilello, J.P., Desrosiers, R.C., Edwards, R., Raab-Traub, N., Cullen, B.R., 2006. Epstein-Barr virus microRNAs are evolutionarily conserved and differentially expressed. PLoS Pathog., 2(3):e23.

[16]Carmilleri-Broet, B.S., Davi, F., Feuillard, J., Bourgeois, C., Seilhean, D., Hauw, J.J., Raphaël, M., 1995. High expression of latent membrane protein 1 of Epstein-Barr virus and BCL-2 oncoprotein in acquired immunodeficiency syndrome-related primary brain lymphomas. Blood, 86(2):432-435.

[17]Choy, E.Y., Siu, K.L., Kok, K.H., Lung, R.W., Tsang, C.M., To, K.F., Kwong, D.L., Tsao, S.W., Jin, D.Y., 2008. An Epstein-Barr virus-encoded microRNA targets PUMA to promote host cell survival. J. Exp. Med., 205(11):2551-2560.

[18]Clybouw, C., McHichi, B., Mouhamad, S., Auffredou, M.T., Bourgeade, M.F., Sharma, S., Leca, G., Vazquez, A., 2005. EBV infection of human B lymphocytes leads to down-regulation of Bim expression: relationship to resistance to apoptosis. J. Immunol., 175(5):2968-2973.

[19]Cohen, J.I., Lekstrom, K., 1999. Epstein-Barr virus BARF1 protein is dispensable for B-cell transformation and inhibits alpha interferon secretion from mononuclear cells. J. Virol., 73(9):7627-7632.

[20]Cory, S., Huang, D.C., Adams, J.M., 2003. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene, 22(53):8590-8607.

[21]Countryman, J., Miller, G., 1985. Activation of expression of latent Epstein-Barr herpesvirus after gene transfer with a small cloned subfragment of heterogeneous viral DNA. PNAS, 82(12):4085-4089.

[22]Cross, J.R., Postigo, A., Blight, K., Downward, J., 2008. Viral pro-survival proteins block separate stages in Bax activation but changes in mitochondrial ultrastructure still occur. Cell Death Differ., 15(6):997-1008.

[23]Danial, N.N., Korsmeyer, S.J., 2004. Cell death: critical control points. Cell, 116(2):205-219.

[24]da Silva, S.R., de Oliveira, D.E., 2011. HIV, EBV and KSHV: viral cooperation in the pathogenesis of human malignancies. Cancer Lett., 305(2):175-185.

[25]Dawson, C.W., Dawson, J., Jones, R., Ward, K., Young, L.S., 1998. Functional differences between BHRF1, the EBV-encoded Bcl-2 homologue, and bcl-2 in human epithelial cells. J. Virol., 72(11):9016-9024.

[26]Desbien, A.L., Kappler, J.W., Marrack, P., 2009. The Epstein-Barr virus Bcl-2 homolog, BHRF1, blocks apoptosis by binding to a limited amount of Bim. PNAS, 106(14):5663-5668.

[27]Feederle, R., Kost, M., Baumann, M., Janz, A., Drouet, E., Hammerschmidt, W., Delecluse, H.J., 2000. The Epstein-Barr virus lytic program is controlled by the co-operative functions of two transactivators. EMBO J., 19(12):3080-3089.

[28]Finke, J., Fritzen, R., Ternes, P., Trivedi, P., Bross, K.J., Lange, W., Mertelsmann, R., Dolken, G., 1992. Expression of bcl-2 in Burkitt’s lymphoma cell lines: induction by latent Epstein-Barr virus genes. Blood, 80(2):459-469.

[29]Flanagan, A.M., Letai, A., 2008. BH3 domains define selective inhibitory interactions with BHRF-1 and KSHV BCL-2. Cell Death Differ., 15(3):580-588.

[30]Forte, E., Luftig, M.A., 2011. The role of microRNAs in Epstein-Barr virus latency and lytic reactivation. Microbes Infect., 13(14-15):1156-1167.

[31]Ghosh, S.K., Perrine, S.P., Faller, D.V., 2012. Advances in virus-directed therapeutics against Epstein-Barr virus-associated malignancies. Adv. Virol., 2012(2012):1-11.

[32]Grundhoff, A., Sullivan, C.S., Ganem, D., 2006. A combined computational and microarray-based approach identifies novel microRNAs encoded by human gamma-herpesviruses. RNA, 12(5):733-750.

[33]Hayes, D.P., Brink, A.A.T., Vervoort, M.B.H.J., Brule, A.J., Middeldorp, J.M., Meijer, C.J.L., 1999. Expression of Epstein-Barr virus (EBV) transcripts encoding homologues to important human proteins in diverse EBV associated diseases. J. Clin. Pathol. Mol., 52(2):97-103.

[34]Hayward, S.D., 2004. Viral interactions with the Notch pathway. Semin. Cancer Biol., 14(5):387-396.

[35]Henderson, S., Huen, D., Rowe, M., Dawson, C., Johnson, G., Rickinson, A., 1993. Epstein-Barr virus-coded BHRF1 protein, a viral homologue of Bcl-2, protects human B cells from programmed cell death. PNAS, 90(18):8479-8483.

[36]Hickish, T., Robertson, D., Clarke, P., Hill, M., Stefano, F., Clarke, C., Cunningham, D., 1994. Ultrastructural localization of BHRF1: an Epstein-Barr virus gene product which has homology with bcl-2. Cancer Res., 54:2808-2811.

[37]Howell, M., Williams, T., Hazlewood, S.A., 2005. Herpesvirus pan encodes a functional homologue of BHRF1, the Epstein-Barr virus v-Bcl-2. BMC Microbiol., 5(6):1-11.

[38]Hsu, S.Y., Lin, P., Hsueh, A.J.W., 1998. BOD (bcl-2-related ovarian death gene) is an ovarian BH3 domain-containing proapoptotic bcl-2 protein capable of dimerization with diverse antiapoptotic bcl-2 members. Mol. Endocrinol., 12(9):1432-1440.

[39]Hsu, S.Y., Kaipia, A., Zhu, L., Hsueh, A.J.W., 1997. Interference of BAD (Bcl-xL/Bcl-2-associated death promoter)-induced apoptosis in mammalian cells by 14-3-3 isoforms and P11. Mol. Endocrinol., 11(12):1858-1867.

[40]Huang, D.C.S., Strasser, A., 2000. BH3-only proteins-essential initiators of apoptotic cell death. Cell, 103(6):839-842.

[41]Jaenisch, R., Bird, A., 2003. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet., 33:245-254.

[42]Jamil, S., Sobouti, R., Hojabrpour, P., Raj, M., Kast, J., Duronio, V., 2005. A proteolytic fragment of Mcl-1 exhibits nuclear localization and regulates cell growth by interaction with Cdk1. Biochem. J., 387(3):659-667.

[43]Jansen, B., Wachek, V., Heere-Ress, E., Schlagbauer-Wadl, H., Hoeller, C., Lucas, T., Hoermann, M., Hollenstein, U., Wolff, K., Pehamberger, H., 2000. Chemosensitization of malignant melanoma by BCL-2 antisense therapy. Lancet, 356(9243):1728-1733.

[44]Kalla, M., Hammerschmidt, W., 2012. Human B cells on their route to latent infection-early but transient expression of lytic genes of Epstein-Barr virus. Eur. J. Cell Biol., 91(1):65-69.

[45]Kalla, M., Schmeinck, A., Bergbauer, M., Pich, D., Hammerschmidt, W., 2010. AP-1 homolog BZLF1 of Epstein-Barr virus has two essential functions dependent on the epigenetic state of the viral genome. PNAS, 107(2):850-855.

[46]Kelly, G.L., Long, H.M., Stylianou, J., Thomas, W.A., Leese, A., Bell, A.I., Bornkamm, G.W., Autner, J.M., Rickinson, A.B., Rowe, M., 2009. An Epstein-Barr virus anti-apoptotic protein constitutively expressed in transformed cells and implicated in Burkitt’s lymphomagenesis: the WP/BHRF1 link. PLoS Pathog., 5(3):e1000341.

[47]Kennedy, G., Komano, J., Sugden, B., 2003. Epstein-Barr virus provides a survival factor to Burkitt’s lymphomas. PNAS, 100(24):14269-14274.

[48]Kenney, J.L., Guinness, M.E., Curiel, T., Lacy, J., 1998. Antisense to the Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP-1) suppresses LMP-1 and bcl-2 expression and promotes apoptosis in EBV-immortalized B cells. Blood, 92(5):1721-1727.

[49]Kim, J.H., Kim, W.S., Park, C., 2012. Epstein-Barr virus latent membrane protein-1 protects B-cell lymphoma from rituximab-induced apoptosis through miR-155-mediated Akt activation and up-regulation of Mcl-1. Leuk. Lymphoma, 53(8):1586-1591.

[50]Kim, L.H., Nadarajah, V.S., Peh, S.C., Poppema, S., 2004. Expression of Bcl-2 family members and presence of Epstein-Barr virus inthe regulation of cell growth and death in classical Hodgkin’s lymphoma. Histopathology, 44(3):257-267.

[51]Klasa, R.J., Bally, M.B., Ng, R., Goldie, J.H., Gascoyne, R.D., Wong, F.M.P., 2000. Eradication of human non-Hodgkin’s lymphoma in SCID mice by BCL-2 antisense oligonucleotides combined with lowdose cyclophosphamide. Clin. Cancer Res., 6:2492-2500.

[52]Kohlhof, H., Hampel, F., Hoffmann, R., Burtscher, H., Weidle, U.H., Hölzel, M., Eick, D., Zimber-Strobl, U., Strobl, L.J., 2009. Notch1, Notch2, and Epstein-Barr virus-encoded nuclear antigen 2 signaling differentially affects proliferation and survival of Epstein-Barr virus-infected B cells. Blood, 113(22):5506-5515.

[53]Komano, J., Sugiura, M., Takada, K., 1998. Epstein-Barr virus contributes to the malignant phenotype and to apoptosis resistance in Burkitt’s lymphoma cell line Akata. J. Virol., 72(11):9150-9156.

[54]Komano, J., Maruo, S., Kurozumi, K., Oda, T., Takada, K., 1999. Oncogenic role of Epstein-Barr virus-encoded RNAs in Burkitt’s lymphoma cell line akata. J. Virol., 73(12):9827.

[55]Kozopas, K.M., Yang, T., Buchan, H.L., Zhou, P., Craig, R.W., 1993. MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2. PNAS, 90(8):3516-3520.

[56]Kvansakul, M., Wei, A.H., Fletcher, J.I., Willis, S.N., Chen, L., 2010. Structural basis for apoptosis inhibition by Epstein-Barr virus BHRF1. PLoS Pathog., 6(12):1-10.

[57]Lantner, F., Starlets, D., Gore, Y., Flaishon, L., Yamit, H.A., Dikstein, R., Leng, L., Bucala, R., Machluf, Y., Oren, M., et al., 2007. CD74 induces TAp63 expression leading to B-cell survival. Blood, 110(13):4303-4311.

[58]Leber, B., Geng, F., Kale, J., Andrews, D.W., 2010. Drugs targeting Bcl2 family members as an emerging strategy in cancer. Exp. Rev. Mol. Med., 12:e18.

[59]Lee, Y.S., Dutta, A., 2009. MicroRNAs in cancer. Ann. Rev. Pathol., 4:199-227.

[60]Letai, A., Bassik, M.C., Walensky, L.D., Sorcinelli, M.D., Weiler, S., Korsmeyer, S.J., 2002. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell, 2(3):183-192.

[61]Li, L.Y., Shih, H.M., Liu, M.Y., Chen, J.Y., 2001. The cellular protein PRA1 modulates the anti-apoptotic activity of Epstein-Barr virus BHRF1, a homologue of Bcl-2, through direct interaction. J. Biol. Chem., 276(29):27354-27362.

[62]Liu, M.T., Chen, Y,R., Chen, S.C., Hu, C.Y., Lin, C.S., Chang, Y.T., Wang, W.B., Chen, J.Y., 2004. Epstein-Barr virus latent membrane protein 1 induces micronucleus formation, represses DNA repair and enhances sensitivity to DNA-damaging agents in human epithelial cells. Oncogene, 23(14):2531-2539.

[63]Liu, M.T., Chang, Y.T., Chen, S.C., Chuang, Y.C., Chen, Y.R., Lin, C.S., Chen, J.Y., 2005. Epstein-Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity. Oncogene, 24(16):2635-2646.

[64]Loomis, R., Carbone, R., Reiss, M., Lacy, J., 2003. Bcl-2 antisense (G3139, Genasense) enhances the in vitro and in vivo response of Epstein-Barr virus-associated lymphoproliferative disease to rituximab. Clin. Cancer Res., 9(5):1931-1939.

[65]Lu, J.Y., Chen, J.Y., Hsu, T.Y., Yu, C.Y., Su, I.J., Yang, C.S., 1997. Cooperative interaction between Bcl-2 and Epstein-Barr virus latent membrane protein 1 in the growth transformation of human epithelial cells. J. Gen. Virol., 78(11):2975-2985.

[66]Marchini, A., Tomkinson, B., Cohen, J.I., Kieff, E., 1991. BHRF1, the Epstein-Barr virus gene with homology to Bcl2, is dispensable for B-lymphocyte transformation and virus replication. J. Virol., 65(11):5991-6000.

[67]Marin, M.C., Hsu, B., Stephens, L.C., Brisbay, S., McDonnell, T.J., 1995. The functional basis of c-myc and bcl-2 complementation during multistep lymphomagenesis in vivo. Exp. Cell Res., 217(2):240-247.

[68]Marshall, W.L., Yim, C., Gustafson, E., Graf, T., Sage, D.R., Hanify, K., Williams, L., Fingeroth, J., Finberg, R.W., 1999. Epstein-Barr virus encodes a novel homolog of the bcl-2 oncogene that inhibits apoptosis and associates with Bax and Bak. J. Virol., 73(6):5181-5185.

[69]McCurrach, M.E., Connor, T.M., Knudson, C.M., Korsmeyer, S.J., Lowe, S.W., 1997. Bax-deficiency promotes drug resistance and oncogenic transformation by attenuating p53-dependent apoptosis. PNAS, 94(6):2345-2349.

[70]Miayake, H., Tolcher, A., Gleave, M.E., 2000. Chemosensitization and delayed androgen-independent recurrence of prostate cancer with the use of antisense Bcl-2 oligodeoxynucleotides. J. Nat. Cancer Inst., 92(1):34-41.

[71]Morris, M.J., Tong, W.P., Cordon-Cardo, C., Drobnjak, M., Kelly, W.K., Slovin, S.F., Terry, K.L., Siedlecki, K., Swanson, P., Rafi, M., et al., 2002. Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer. Clin. Cancer Res., 8:679-683.

[72]Nakano, K., Vousden, K.H., 2001. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell, 7(3):683-694.

[73]Nguyen, M., Marcellus, R.C., Roulston, A., Watson, M., Serfass, L., Madiraju, S.R.M., Goulet, D., Viallet, J., Bélec, L., Billot, X., et al., 2007. Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis. PNAS, 104(49):19512-19517.

[74]Noguchi, T., Ikeda, K., Yamamoto, K., Yoshida, I., Ashiba, A., Tsuchiyama, J., Shinagawa, K., Yoshino, T., Takata, M., Harada, M., 2001. Antisense oligodeoxynucleotides to latent membrane protein 1 induce growth inhibition, apoptosis and Bcl-2 suppression in Epstein-Barr virus EBV-transformed B-lymphoblastoid cells, but not in EBV-positive natural killer cell lymphoma cells. Br. J. Haematol., 114(1):84-92.

[75]Paschos, K., Smith, P., Anderton, E., Middeldorp, J.M., White, R.E., Allday, M.J., 2009. Epstein-Barr virus latency in B cells leads to epigenetic repression and CpG methylation of the tumor suppressor gene bim. PLoS Pathogens., 5(6):e1000492.

[76]Paschos, K., Parker, G.A., Watanatanasup, E., White, R.E., Allday, M.J., 2012. BIM promoter directly targeted by EBNA3C in polycomb-mediated repression by EBV. Nucleic Acids Res., 40(15):7233-7246.

[77]Pegman, P.M., Smith, S.M., D'Souza, B.N., Loughran, S.T., Maier, S., Kempkes, B., Cahill, P.A., Gélinas, C., Simmons, M.J., Walls, D., 2006. Epstein-Barr virus nuclear antigen 2 trans-activates the cellular anti-apoptotic bfl-1 gene by a CBF1/RBPJk-dependent pathway. J. Virol., 80(16):8133-8144.

[78]Pfeffer, S., Zavolan, M., Grasser, F.A., Chien, M., Russo, J.J., Ju, J., John, B., Enright, J., Marks, D., Sander, C., et al., 2004. Identification of virus-encoded microRNAs. Science, 304(5671):734-736.

[79]Portis, T., Longnecker, R., 2004. Epstein-Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/AKT pathway. Oncogene, 23(53):8619-8628.

[80]Pratt, Z.L., Zhang, J., Sugden, B., 2012. Simultaneously induce and inhibit oncogene of Epstein-Barr virus can the latent membrane protein 1 (LMP1) apoptosis in B cells. J. Virol., 86(8):4380.

[81]Pujals, A., Renouf, B., Robert, A., Chelouah, S., Hollville, E., Wiels, J., 2011. Treatment with a BH3 mimetic overcomes the resistance of latency III EBV(+) cells to p53-mediated apoptosis. Cell Death Dis., 2(7):e184.

[82]Puthalakath, H., Strasser, A., 2002. Keeping killers on a tight leash: transcriptional and post-translational control of the pro-apoptotic activity of BH3-only proteins. Cell Death Differ., 9(5):505-512.

[83]Rampino, N., Yamamoto, H., Ionov, Y., Li, Y., Sawai, H., Reed, J.C., Perucho, M., 1997. Somatic frame shift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science, 275(5303):967-969.

[84]Rickinson, A.B., Kieff, E., 2007. Epstein-Barr virus. J. Virol., 2655-2700.

[85]Rickinson, A.B., Kieff, E., 2007. Epstein-Barr Virus. In: Knipe, D.M., Howley, P.M., (Eds.), Fields of virology. Lippincott Williams & Wilkins, Philadelphia, PA, p.2655-2700

[86]Riedl, S.J., Shi, Y., 2004. Molecular mechanisms of caspase regulation during apoptosis. Nat. Rev. Mol. Cell. Biol., 5(11):897-907.

[87]Rowe, M., Peng-Pilon, M., Huen, D.S., Hardy, R., Croom-Carter, D., Lundgren, E., Rickinson, A.B., 1994. Up-regulation of bcl-2 by the Epstein-Barr virus latent membrane protein LMP1: a B-cell-specific response that is delayed relative to NF-κB activation and to induction of cell surface markers. J. Virol., 68(9):5602-5612.

[88]Sarac, S., Akyol, M.U., Kanbur, B., Poyraz, A., Akyol, G., Yilmaz, T., Sungur, A., 2001. Bcl-2 and LMP1 expression in nasopharyngeal carcinomas. Am. J. Otolaryng., 22(6):377-382.

[89]Scholle, F., Bendt, K.M., Raab-Traub, N., 2000. Epstein-Barr virus LMP2A transforms epithelial cells, inhibits cell differentiation, and activates Akt. J. Virol., 74(22):10681-10689.

[90]Sheng, W., Decaussin, G., Sumner, S., Ooka, T., 2001. N-terminal domain of BARF1 gene encoded by Epstein-Barr virus is essential for malignant transformation of rodent fibroblasts and activation of BCL-2. Oncogene, 20(10):1176-1185.

[91]Sheng, W., Decaussin, G., Ligout, A., Takada, K., Ooka, T., 2003. Malignant transformation of Epstein-Barr virus-negative akata cells by introduction of the BARF1 gene carried by Epstein-Barr virus. J. Virol., 77(6):3859-3865.

[92]Sinclair, A.J., 2003. bZIP proteins of human gammaherpesviruses. J. Gen. Virol., 84(8):1941-1949.

[93]Spender, L.C., Inman, G.J., 2011. Inhibition of germinal center apoptotic programmes by Epstein-Barr virus. Adv. Hematol., 2011:1-10.

[94]Srimatkandada, P., Loomis, R., Carbone, R., Srimatkandada, S., Lacy, J., 2008. Combined proteasome and Bcl-2 inhibition stimulates apoptosis and inhibits growth in EBV-transformed lymphocytes: a potential therapeutic approach to EBV-associated lymphoproliferative diseases. Eur. J. Haematol., 80(5):407-418.

[95]Steelman, L.S., Pohnert, S.C., Shelton, J.G., Franklin, R.A., Bertrand, F.E., McCubrey, J.A., 2004. JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis. Leukemia, 18(2):189-218.

[96]Strockbine, L.D., Cohen, J.I., Farrah, T., Lyman, S.D., Wagener, F., DuBose, R.F., Armitage, R.J., Spriggs, M.K., 1998. The Epstein-Barr virus BARF1 gene encodes a novel, soluble colony-stimulating factor-1 receptor. J. Virol., 72(5):4015-4021.

[97]Suzuki, M.M., Bird, A., 2008. DNA methylation landscapes: provocative insights from epigenomics. Nat. Rev. Genet., 9(6):465-476.

[98]Swanson-Mungerson, M., Bultema, R., Longnecker, R., 2010. Epstein-Barr virus LMP2A imposes sensitivity to apoptosis. J. Gen. Virol., 91(9):2197-2202.

[99]Takano, Y., Saegusa, M., Masuda, M., Mikami, T., Okayasu, I., 1997. Apoptosis, proliferative activity and Bcl-2 expression in Epstein-Barr-virus-positive non-Hodgkin’s lymphoma. J. Cancer Res. Clin., 123(7):395-401.

[100]Theodorakis, P., D′Sa-Eipper, C., Subramanian, T., Chinnadurai, G., 1996. Unmasking of a proliferation-restraining activity of the anti-apoptosis protein EBV BHRF. Oncogene, 12(8):1707-1713.

[101]Thorley-Lawson, D.A., Gross, A., 2004. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N. Engl. J. Med., 350(13):1328-1337.

[102]Tomkinson, B., Robertson, E., Kieff, E., 1993. Epstein-Barr virus nuclear proteins EBNA-3A and EBNA-3C are essential for B-lymphocyte growth transformation. J. Virol., 67(4):2014-2025.

[103]Vogler, M., Butterworth, M., Majid, A., Walewska, R.J., Sun, X.M., Dyer, M.J.S., Cohen, G.M., 2009. Concurrent up-regulation of BCL-XL and BCL2A1 induces approximately 1000-fold resistance to ABT-737 in chronic lymphocytic leukemia. Blood, 113(18):4403-4413.

[104]Wachek, V., Heere-Ress, E., Halaschek-Wiener, J., Lucas, T., Meyer, H., Eichler, H.G., Jansen, B., 2001. Bcl-2 antisense oligonucleotides chemosensitize human gastric cancer in a SCID mouse xenotransplantation model. J. Mol. Med., 79(10):587-593.

[105]Wang, S., Rowe, M., Lundgren, E., 1996. Expression of the Epstein Barr virus transforming protein LMP1 causes a rapid and transient stimulation of the Bcl-2 homologue Mcl-1 levels in B-cell lines. Cancer Res., 56:4610-4613.

[106]Waters, J.S., Webb, A., Cunningham, D., Clarke, P.A., Raynaud, F., di Stefano, F., Cotter, F.E., 2000. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma. J. Clin. Oncol., 18(9):1812-1823.

[107]Wei, M.C., Zong, W.X., Cheng, E.H., Lindsten, T., Panoutsakopoulou, V., Ross, A.J., Roth, K.A., MacGregor, G.R., Thompson, C.B., Korsmeyer, S.J., 2001. Pro-apoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science, 292(5517):727-730.

[108]White, E., 1996. Life, death, and the pursuit of apoptosis. Gen. Dev., 10(1):1-15.

[109]Wong, H.L., Wang, X., Chang, R.C., Jin, D.Y., Feng, H., Wang, Q., Lo, K.W., Huang, D.P., Yuen, P.W., Takada, K., et al., 2005. Stable expression of EBERs in immortalized nasopharyngeal epithelial cells confers resistance to apoptotic stress. Mol. Carcinogen., 44(2):92-101.

[110]Wu, D., Wallen, H.D., Nunez, G., 1997. Interaction and regulation of subcellular localization of CED-4 by CED-9. Science, 275(5303):1126-1129.

[111]Xu, Z.G., Iwatsuki, K., Oyama, N., Ohtsuka, M., Satoh, M., Kikuchi, S., Akiba, H., Kaneko, F., 2001. The latency pattern of Epstein-Barr virus infection and viral IL-10 expression in cutaneous natural killer/T cell lymphomas. Br. J. Cancer, 84(7):920-925.

[112]Yakovlev, A.G., Giovanni, S.D., Wang, G., Liu, W., 2004. BOK and NOXA are essential mediators of p53-dependentapoptosis. J. Biol. Chem., 279(27):28367-28374.

[113]Yin, C., Knudson, C.M., Korsmeyer, S.J., van Dyke., T., 1997. Bax suppresses tumorigenesis and stimulates apoptosis in vivo. Nature, 385(6617):637-640.

[114]Yu, J., Zhang, L., Hwang, P.M., Kinzler, K.W., Vogelstein, B., 2001. PUMA induces the rapid apoptosis of colorectal cancer cells. Mol. Cell, 7(3):673-682.

[115]Zhang, C.Z., Zhang, J.X., Zhang, L.A., Shi, Z.D., Han, L., Jia, Z.F., Yang, W.D., Wang, G.X., Jiang, T., You, Y.P., et al., 2010. MiR-221 and miR-222 target PUMA to induce cell survival in glioblastoma. Mol. Cancer, 9(299):1-9.

[116]Zimber-Strobl, U., Strobl, L.J., 2001. EBNA2 and Notch signaling in Epstein-Barr virus mediated immortalization of B lymphocytes. Semin. Cancer Biol., 11(6):423-434.

[117]Zinkel, S., Gross, A., Yang, E., 2006. BCL2 family in DNA damage and cell cycle control. Cell Death Differ., 13(8):1351-1359.

[118]Zong, W.X., Lindsten, T., Ross, A.J., MacGregor, G.R., Thompson, C.B., 2001. BH3-only proteins that bind pro-survival Bcl-2 family members fail to induce apoptosis in the absence of Bax and Bak. Gene Dev., 15(12):1481-1486.

[119]Zou, H., Henzel, W.J., Liu, X., Lutschg, A., Wang, X., 1997. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell, 90(3):405-413.

[120]Zuo, J., Thomas, W.A., Haigh, T.A., Fitzsimmons, L., Long, H.M., Hislop, A.D., Taylor, G.S., Rowe, M., 2011. Epstein-Barr virus evades CD4+ T cell responses in lytic cycle through BZLF1-mediated down-regulation of CD74 and the cooperation of vBcl-2. PLoS Pathog., 7(12):e1002455.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2022 Journal of Zhejiang University-SCIENCE