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Epstein–Barr virus-encoded EBNA1 regulates cellular gene transcription and modulates the STAT1 and TGFβ signaling pathways

Oncogene volume 26, pages 4135–4147 (2007)Cite this article

Abstract

The Epstein–Barr virus (EBV)-encoded EBNA1 protein is expressed in all virus-associated tumors where it plays an essential role in the maintenance, replication and transcription of the EBV genome. Transcriptional profiling of EBNA1-expressing carcinoma cells demonstrated that EBNA1 also influences the expression of a range of cellular genes including those involved in translation, transcription and cell signaling. Of particular interest was the ability of EBNA1 to enhance expression of STAT1 and sensitize cells to interferon-induced STAT1 activation with resultant enhancement of major histocompatibility complex expression. A negative effect of EBNA1 on the expression of TGFβ1-responsive βig-h3 and PAI-1 genes was confirmed at the protein level in EBV-infected carcinoma cells. This effect resulted from the ability of EBNA1 to repress TGFβ1-induced transcription via a reduction in the interaction of SMAD2 with SMAD4. More detailed analysis revealed that EBNA1 induces a lower steady-state level of SMAD2 protein as a consequence of increased protein turnover. These data show that EBNA1 can influence cellular gene transcription resulting in effects that may contribute to the development of EBV-associated tumors.

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References

  • Balkwill F, Mantovani A . (2001). Inflammation and cancer: back to Virchow? Lancet 357: 539–545.

    Article  CAS  PubMed  Google Scholar 

  • Baumforth KRN, Flavell JR, Reynolds GM, Davies G, Pettitt TR, Wei WB et al. (2005). Induction of autotaxin by the Epstein–Barr virus promotes the growth and survival of Hodgkin's lymphoma cells. Blood 106: 2138–2146.

    Article  CAS  PubMed  Google Scholar 

  • Cao WP, Tan P, Lee CH, Zhang HF, Lu JH . (2006). A transforming growth factor-β-induced protein stimulates endocytosis and is up-regulated in immature dendritic cells. Blood 107: 2777–2785.

    Article  CAS  PubMed  Google Scholar 

  • Chen H, Hutt-Fletcher LM, Cao L, Hayward SD . (2003). A positive autoregulatory loop of LMP1 expression and STAT activation in epithelial cells latently infected with Epstein–Barr virus. J Virol 77: 4139–4148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen H, Lee JM, Zong YS, Borowitz M, Ng MH, Ambinder RF et al. (2001). Linkage between STAT regulation and Epstein–Barr virus gene expression in tumours. J Virol 75: 2929–2937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen HL, Lee JM, Wang YL, Huang DP, Ambinder RF, Hayward SD . (1999). The Epstein–Barr virus latency BamHI-Q promoter is positively regulated by STATs and Zta interference with JAK/STAT activation leads to loss of BamHI-Q promoter activity. Proc Natl Acad Sci USA 96: 9339–9344.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choi SH, Hwang SB . (2006). Modulation of the transforming growth factor-β signal transduction pathway by hepatitis C virus nonstructural 5A protein. J Biol Chem 281: 7468–7478.

    Article  CAS  PubMed  Google Scholar 

  • Chow LS, Lam CW, Chan SY, Tsao SW, To KF, Tong S-F et al. (2006). Identification of RASSF1A modulated genes in nasopharyngeal carcinoma. Oncogene 25: 310–316.

    Article  CAS  PubMed  Google Scholar 

  • Chuang TC, Way TD, Lin YS, Lee YC, Law SL, Kao MC . (2002). The Epstein–Barr virus nuclear antigen-1 may act as a transforming suppressor of the HER2/neu oncogene. FEBS Lett 532: 135–142.

    Article  CAS  PubMed  Google Scholar 

  • Debonneville C, Staub O . (2004). Participation of the ubiquitin-conjugating enzyme UBE2E3 in Nedd4-2-dependent regulation of the epithelial Na+ channel. Mol Cell Biol 24: 2397–2409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fakhari FD, Jeong JH, Kanan Y, Dittmer DP . (2006). The latency-associated nuclear antigen of Kaposi sarcoma-associated herpesvirus induces B cell hyperplasia and lymphoma. J Clin Invest 116: 735–742.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Friborg J, Kong WP, Hottinger MO, Nabel GJ . (1999). p53 inhibition by the LANA protein of KSHV protects against cell death. Nature 402: 889–894.

    Article  CAS  PubMed  Google Scholar 

  • Fujimuro M, Wu FY, ApRhys C, Kajumbula H, Young DB, Hayward GS et al. (2003). A novel viral mechanism for dysregulation of β-catenin in Kaposi's sarcoma-associated herpesvirus latency. Nat Med 9: 300–306.

    Article  CAS  PubMed  Google Scholar 

  • Fukuda M, Longnecker R . (2004). Latent membrane protein 2A inhibits transforming growth factor-β1-induced apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. J Virol 78: 1697–1705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta A, Gartner JJ, Sethupathy P, Hatzigeorgiou AG, Fraser NW . (2006). Anti-apoptotic function of a microRNA encoded by the HSV-1 latency-associated transcript. Nature 442: 82–85.

    Article  CAS  PubMed  Google Scholar 

  • Haider AS, Peters SB, Kaporis H, Cardinale I, Fei J, Ott J et al. (2006). Genomic analysis defines a cancer-specific gene expression signature for human squamous cell carcinoma and distinguishes malignant hyperproliferation from benign hyperplasia. J Invest Dermatol 126: 869–881.

    Article  CAS  PubMed  Google Scholar 

  • Harn HJ, Fan HC, Chen CJ, Tsai NM, Yen CY, Huang SC . (2002). Microsatellite alteration at chromosome 11 in primary human nasopharyngeal carcinoma in Taiwan. Oral Oncol 38: 23–29.

    Article  CAS  PubMed  Google Scholar 

  • Holowaty MN, Zeghouf M, Wu H, Tellam J, Athanasopoulos V, Greenblatt J et al. (2003). Protein profiling with Epstein–Barr nuclear antigen-1 reveals an interaction with the herpesvirus-associated ubiquitin-specific protease HAUSP/USP7. J Biol Chem 278: 29987–29994.

    Article  CAS  PubMed  Google Scholar 

  • Huibregtse JM, Scheffner M, Howley PM . (1991). A cellular protein mediates association of P53 with the E6 oncoprotein of human papillomavirus type-16 or type-18. EMBO J 10: 4129–4135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Humme S, Reisbach G, Feederle R, Delecluse HJ, Bousset K, Hammerschmidt W et al. (2003). The EBV nuclear antigen1 (EBNA1) enhances B cell immortalisation several thousand-fold. Proc Natl Acad Sci USA 100: 10989–10994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang MS, Hung SC, Kieff E . (2001). Epstein–Barr virus nuclear antigen 1 activates transcription from episomal but not integrated DNA and does not alter lymphocyte growth. Proc Natl Acad Sci USA 98: 15233–15238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kang MS, Lu HX, Yasui T, Sharpe A, Warren H, Cahir-McFarland E et al. (2005). Epstein–Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice. Proc Natl Acad Sci USA 102: 820–825.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kennedy G, Komano J, Sugden B . (2003). Epstein–Barr virus provides a survival factor to Burkitt's lymphomas. Proc Natl Acad Sci USA 100: 14269–14274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kieff E, Rickinson AB . (2001). Epstein–Barr virus and its replication. In: Knipe Dm, Howley Pm (eds). Fields Virology. Lippincott Williams & Wilkins: Philadelphia, pp 2511–2574.

    Google Scholar 

  • 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: 9150–9156.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kovacic B, Stoiber D, Moriggl R, Weisz E, Ott RG, Kreibich R et al. (2006). STAT1 acts as a tumor promoter for leukemia development. Cancer Cell 10: 77–87.

    Article  CAS  PubMed  Google Scholar 

  • Kube D, Vockerodt M, Weber O, Hell K, Wolf J, Haier B et al. (1999). Expression of Epstein–Barr virus nuclear antigen 1 is associated with enhanced expression of CD25 in the Hodgkin cell line L428. J Virol 73: 1630–1636.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kuratomi G, Komuro A, Goto K, Shinozaki M, Miyazawa K, Miyazono K et al. (2005). NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-β (transforming growth factor-β) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-β type I receptor. Biochem J 386: 461–470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee DK, Kim BC, Kim IY, Cho EA, Satterwhite DJ, Kim SJ . (2002). The human papilloma virus E7 oncoprotein inhibits transforming growth factor-beta signaling by blocking binding or the Smad complex to its target sequence. J Biol Chem 277: 38557–38564.

    Article  CAS  PubMed  Google Scholar 

  • Lee SP, Brooks JM, Al-Jarrah H, Thomas WA, Haigh RT, Taylor GS et al. (2004). CD8T cell recognition of endogenously expressed Epstein–Barr virus nuclear antigen 1. J Exp Med 199: 1409–1420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Levitskaya J, Coram M, Levitsky V, Imreh S, Steigerwald-Mullen P, Masucci MG . (1995). Inhibition of antigen processing by the internal repeat region of the Epstein–Barr virus nuclear antigen-1. Nature 375: 685–688.

    Article  CAS  PubMed  Google Scholar 

  • Liang CL, Chen JL, Hsu YPP, Ou JT, Chang YS . (2002). Epstein–Barr virus BZLF1 gene is activated by transforming growth factor-β through cooperativity of Smads and c-Jun/c-Fos proteins. J Biol Chem 277: 23345–23357.

    Article  CAS  PubMed  Google Scholar 

  • Liang CL, Tsai CN, Chung PJ, Chen JL, Sun CM, Chen RH et al. (2000). Transcription of Epstein–Barr virus-encoded nuclear antigen 1 promoter Qp is repressed by transforming growth factor-beta via Smad4 binding element in human BL cells. Virology 277: 184–192.

    Article  CAS  PubMed  Google Scholar 

  • Lo RS, Massague J . (1999). Ubiquitin-dependent degradation of TGF-β-activated Smad2. Nat Cell Biol 1: 472–478.

    Article  CAS  PubMed  Google Scholar 

  • Mori N, Morishita M, Tsukazaki T, Yamamoto N . (2003). Repression of SMAD-dependent transforming growth factor-β signaling by Epstein–Barr virus latent membrane protein 1 through nuclear factor-κβ. Int J Cancer 105: 661–668.

    Article  CAS  PubMed  Google Scholar 

  • Munier FL, Korvatska E, Djemai A, LePaslier D, Zografos L, Pescia G et al. (1997). Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet 15: 247–251.

    Article  CAS  PubMed  Google Scholar 

  • Nam JO, Jeong HW, Lee BH, Park RW, Kim IS . (2005). Regulation of tumor angiogenesis by fastatin, the fourth FAS1 domain of βig-h3 via αvβ3 integrin. Cancer Res 65: 4153–4161.

    Article  CAS  PubMed  Google Scholar 

  • Oh JE, Kook JK, Min BM . (2005). Big-h3 induces keratinocyte differentiation via modulation of involucrin and transglutaminase expression through the integrin α3β1 and the phosphatidylinositol 3-kinase/Akt signaling pathway. J Biol Chem 280: 21629–21637.

    Article  CAS  PubMed  Google Scholar 

  • Perk J, Iavarone A, Benezra R . (2005). ID family of helix–loop–helix proteins in cancer. Nat Rev Cancer 5: 603–605.

    Article  CAS  PubMed  Google Scholar 

  • Raab-Traub N . (2002). Epstein–Barr virus in the pathogenesis of NPC. Semin Cancer Biol 12: 431–441.

    Article  CAS  PubMed  Google Scholar 

  • Radkov SA, Kellam P, Boshoff C . (2000). The latent nuclear antigen of Kaposi's sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene HRAS transforms primary rat cells. Nat Med 6: 1121–1127.

    Article  CAS  PubMed  Google Scholar 

  • Renne C, Martin-Subero JI, Eickernjager M, Hansmann ML, Kuppers R, Siebert R et al. (2006). Aberrant expression of ID2, a suppressor of B-cell specific gene expression, in Hodgkin's lymphoma. Am J Pathol 169: 655–664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rickinson AB, Kieff E . (2001). Epstein–Barr virus. In: Knipe Dm, Howley Pm (eds). Fields Virology. Lippincott Williams and Wilkins: Philadelphia, pp 2575–2627.

    Google Scholar 

  • Ruf IK, Rhyne PW, Yang C, Cleveland JL, Sample JT . (2000). Epstein–Barr virus small RNAs potentiate tumourigenicity of Burkitt lymphoma cells independently of an effect on apoptosis. J Virol 74: 10223–10228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saridakis V, Sheng Y, Sarkari F, Holowaty MN, Shire K, Nguyen T et al. (2005). Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein–Barr nuclear antigen 1: implications for EBV-mediated immortalization. Mol Cell 18: 25–36.

    Article  CAS  PubMed  Google Scholar 

  • Seo TG, Park JS, Choe JH . (2005). Kaposi's sarcoma – associated herpesvirus viral IFN regulatory factor 1 inhibits transforming growth factor-β signaling. Cancer Res 65: 1738–1747.

    Article  CAS  PubMed  Google Scholar 

  • Shao GZ, Berenguer J, Borczuk AC, Powell CA, Hei TK, Zhao YL . (2006). Epigenetic inactivation of Betaig-h3 gene in human cancer cells. Cancer Res 66: 4566–4573.

    Article  CAS  PubMed  Google Scholar 

  • Sheng Y, Saridakis V, Sarkari F, Duan SL, Wu TN, Arrowsmith CH et al. (2006). Molecular recognition of p53 and MDM2 by USP7/HAUSP. Nat Struct Mol Biol 13: 285–291.

    Article  CAS  PubMed  Google Scholar 

  • Sheu LF, Meng CL, Ho KC, Lee WH, Leu FJ, Chao CF . (1996). Enhanced malignant progression of nasopharyngeal carcinoma cells mediated by the expression of Epstein–Barr nuclear antigen 1 in vivo. J Pathol 180: 243–248.

    Article  CAS  PubMed  Google Scholar 

  • Siegel PM, Massague J . (2003). Cytostatic and apoptotic actions of TGF-beta in homeostasis and cancer. Nat Rev Cancer 3: 807–820.

    Article  CAS  PubMed  Google Scholar 

  • Srinivas SK, Sixbey JW . (1995). Epstein–Barr-virus induction of recombinase-activating genes Rag1 and Rag2. J Virol 69: 8155–8158.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stewart S, Dawson CW, Takada K, Curnow J, Moody CA, Sixbey JW et al. (2004). Epstein–Barr virus encoded LMP2A regulates viral and cellular gene expression via modulation of the NF-κB transcription factor pathway. Proc Natl Acad Sci USA 101: 15730–15735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tellam J, Connolly G, Green KJ, Miles JJ, Moss DJ, Burrows SR et al. (2004). Endogenous presentation of CD8(+) T cell epitopes from Epstein–Barr virus-encoded nuclear antigen 1. J Exp Med 199: 1421–1431.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsimbouri P, Drotar ME, Coy JL, Wilson JB . (2002). bcl-x(L) and RAG genes are induced and the response to IL-2 enhanced in E mu EBNA-1 transgenic mouse lymphocytes. Oncogene 21: 5182–5187.

    Article  CAS  PubMed  Google Scholar 

  • Tusher VG, Tibshirani R, Chu G . (2001). Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci USA 98: 5116–5121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Voo KS, Fu TH, Wang HY, Tellam J, Heslop HE, Brenner MK et al. (2004). Evidence for the presentation of major histocompatibility complex class I-restricted Epstein–Barr virus nuclear antigen 1 peptides to CD8(+) T lymphocytes. J Exp Med 199: 459–470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson JB, Bell JL, Levine AJ . (1996). Expression of Epstein–Barr virus nuclear antigen-1 induces B cell neoplasia in transgenic mice. EMBO J 15: 3117–3126.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xi SC, Dyer KF, Kimak M, Zhang Q, Gooding WE, Chaillet JRD et al. (2006). Decreased STAT1 expression by promoter methylation in squamous cell carcinogenesis. J Natl Cancer Inst 98: 181–189.

    Article  CAS  PubMed  Google Scholar 

  • Young LS, Rickinson AB . (2004). Epstein–Barr virus: 40 years on. Nat Rev Cancer 4: 757–768.

    Article  CAS  PubMed  Google Scholar 

  • Yu H, Jove R . (2004). The stats of cancer – new molecular targets come of age. Nat Rev Cancer 4: 97–105.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by Cancer Research UK and the European Commission's FP6 Life-Sciences-Health Programme (INCA Project: LSHC-CT-2005-018704). We thank Joan Massague for providing reagents and Dolly Huang for providing the C666-1 cell line.

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  1. Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, UK

    V H J Wood, J D O'Neil, W Wei, S E Stewart, C W Dawson & L S Young

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Correspondence to L S Young.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Wood, V., O'Neil, J., Wei, W. et al. Epstein–Barr virus-encoded EBNA1 regulates cellular gene transcription and modulates the STAT1 and TGFβ signaling pathways. Oncogene 26, 4135–4147 (2007). https://doi.org/10.1038/sj.onc.1210496

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