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  • Original Article
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EBV EBNA 2 stimulates CDK9-dependent transcription and RNA polymerase II phosphorylation on serine 5

Oncogene volume 25, pages 1775–1785 (2006)Cite this article

Abstract

EBNA 2 is one of only five viral genes essential for the infection and immortalization of human B cells by the cancer-associated virus Epstein-Barr virus (EBV). EBNA 2 activates cellular and viral transcription and associates with components of the basal transcription apparatus and a number of coactivators. We provide the first evidence to show that the mechanism of transcriptional activation by EBNA 2 also involves phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (pol II). We found that transcriptional activation by EBNA 2 was inhibited by a dominant-negative mutant of the pol II CTD kinase, CDK9, and by low concentrations of the CDK9 inhibitor 5, 6-dichloro-1-β-D-ribofuranosylbenzimidazole. Moreover, using chromatin immunoprecipitation assays we demonstrated that EBNA 2 stimulates both pol II recruitment and pol II phosphorylation on serine 5 of the CTD in vivo. These results identify a new step in the transcription cycle that is subject to regulation by a key EBV-encoded transcription factor and highlight CDK9 inhibitors as potential anti-EBV agents.

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References

  • Abbot SD, Rowe M, Cadwallader K, Ricksten A, Gordon J, Wang F et al. (1990). J Virol 64: 2126–2134.

  • Alazard N, Gruffat H, Hiriart E, Sergeant A, Manet E . (2003). J Virol 77: 8166–8172.

  • Alfieri C, Birkenbach M, Kieff E . (1991). Virology 181: 595–608.

  • Allday MJ, Crawford DH, Griffin BE . (1989). J Gen Virol 70 (Part 7): 1755–1764.

  • Andersson J . (2000). Herpes 7: 76–82.

  • Chao SH, Price DH . (2001). J Biol Chem 276: 31793–31799.

  • Chao SH, Fujinaga K, Marion JE, Taube R, Sausville EA, Senderowicz AM et al. (2000). J Biol Chem 275: 28345–28348.

  • Cohen JI, Kieff E . (1991). J Virol 65: 5880–5885.

  • Cohen JI . (1992). Proc Natl Acad Sci USA 89: 8030–8034.

  • Cohen JI, Wang F, Mannick J, Kieff E . (1989). Proc Natl Acad Sci USA 86: 9558–9562.

  • Decker RH, Dai Y, Grant S . (2001). Cell Death Differ 8: 715–724.

  • Deng Z, Atanasiu C, Burg JS, Broccoli D, Lieberman PM . (2003). J Virol 77: 11992–12001.

  • Dubois MF, Nguyen VT, Bellier S, Bensaude O . (1994). J Biol Chem 269: 13331–13336.

  • Eberhardy SR, Farnham PJ . (2002). J Biol Chem 277: 40156–40162.

  • Gold MO, Tassan JP, Nigg EA, Rice AP, Herrmann CH . (1996). Nucl Acids Res 24: 3771–3777.

  • Gold MO, Yang X, Herrmann CH, Rice AP . (1998). J Virol 72: 4448–4453.

  • Grossman SR, Johannsen E, Tong X, Yalamanchili R, Kieff E . (1994). Proc Natl Acad Sci USA 91: 7568–7572.

  • Henkel T, Ling PD, Hayward SD, Peterson MG . (1994). Science 265: 92–95.

  • Herrmann CH, Gold MO, Rice AP . (1996). Nucl Acids Res 24: 501–508.

  • Isel C, Karn J . (1999). J Mol Biol 290: 929–941.

  • Johannsen E, Koh E, Mosialos G, Tong X, Kieff E, Grossman SR . (1995). J Virol 69: 253–262.

  • Kaye KM, Izumi KM, Kieff E . (1993). Proc Natl Acad Sci USA 90: 9150–9154.

  • Kempkes B, Spitkovsky D, Jansen-Durr P, Ellwart JW, Kremmer E, Delecluse HJ et al. (1995). EMBO J 14: 88–96.

  • Kim YK, Bourgeois CF, Isel C, Churcher MJ, Karn J . (2002). Mol Cell Biol 22: 4622–4637.

  • Komarnitsky P, Cho EJ, Buratowski S . (2000). Genes Dev 14: 2452–2460.

  • Lee DK, Duan HO, Chang C . (2001). J Biol Chem 276: 9978–9984.

  • Lee MA, Diamond ME, Yates JL . (1999). J Virol 73: 2974–2982.

  • Ling PD, Rawlins DR, Hayward SD . (1993). Proc Natl Acad Sci USA 90: 9237–9241.

  • Litz J, Carlson P, Warshamana-Greene GS, Grant S, Krystal GW . (2003). Clin Cancer Res 9: 4586–4594.

  • Ma Y, Cress WD, Haura EB . (2003). Mol Cancer Ther 2: 73–81.

  • Makela TP, Tassan JP, Nigg EA, Frutiger S, Hughes GJ, Weinberg RA . (1994). Nature 371: 254–257.

  • Marshall NF, Peng J, Xie Z, Price DH . (1996). J Biol Chem 271: 27176–27183.

  • Nelson PJ, D'Agati VD, Gries JM, Suarez JR, Gelman IH . (2003). J Antimicrob Chemother 51: 921–929.

  • Palancade B, Bensaude O . (2003). Eur J Biochem 270: 3859–3870.

  • Patel V, Senderowicz AM, Pinto Jr D, Igishi T, Raffeld M, Quintanilla-Martinez L et al. (1998). J Clin Invest 102: 1674–1681.

  • Ping YH, Rana TM . (1999). J Biol Chem 274: 7399–7404.

  • Ramanathan Y, Rajpara SM, Reza SM, Lees E, Shuman S, Mathews MB et al. (2001). J Biol Chem 276: 10913–10920.

  • Sadaie MR, Mayner R, Doniger J . (2004). Antiviral Res 61: 1–18.

  • Sedlacek HH . (2001). Crit Rev Oncol Hematol 38: 139–170.

  • Sjoblom A, Jansson A, Yang W, Lain S, Nilsson T, Rymo L . (1995). J Gen Virol 76 (Part 11): 2679–2692.

  • Skare J, Farley J, Strominger JL, Fresen KO, Cho MS, zur Hausen H . (1985). J Virol 55: 286–297.

  • Spilianakis C, Kretsovali A, Agalioti T, Makatounakis T, Thanos D, Papamatheakis J . (2003). EMBO J 22: 5125–5136.

  • Swaminathan S . (1996). Virology 217: 532–541.

  • Tian Y, Ke S, Chen M, Sheng T . (2003). J Biol Chem 278: 44041–44048.

  • Tomkinson B, Robertson E, Kieff E . (1993). J Virol 67: 2014–2025.

  • Tong X, Drapkin R, Reinberg D, Kieff E . (1995a). Proc Natl Acad Sci USA 92: 3259–3263.

  • Tong X, Drapkin R, Yalamanchili R, Mosialos G, Kieff E . (1995b). Mol Cell Biol 15: 4735–4744.

  • Tong X, Wang F, Thut CJ, Kieff E . (1995c). J Virol 69: 585–588.

  • Tsang SF, Wang F, Izumi KM, Kieff E . (1991). J Virol 65: 6765–6771.

  • Van Veldhuizen PJ, Faulkner JR, Lara Jr PN, Gumerlock PH, Goodwin JW, Dakhil SR et al. (2005). Cancer Chemother Pharmacol 56: 39–45.

  • Waltzer L, Logeat F, Brou C, Israel A, Sergeant A, Manet E . (1994). EMBO J 13: 5633–5638.

  • Wang F, Tsang SF, Kurilla MG, Cohen JI, Kieff E . (1990). J Virol 64: 3407–3416.

  • Wang L, Grossman SR, Kieff E . (2000). Proc Natl Acad Sci USA 97: 430–435.

  • Wendtner CM, Eichhorst BF, Hallek MJ . (2004). Semin Hematol 41: 224–233.

  • West MJ, Karn J . (1999). EMBO J 18: 1378–1386.

  • West MJ, Webb HM, Sinclair AJ, Woolfson DN . (2004). J Virol 78: 9431–9445.

  • Woisetschlaeger M, Jin XW, Yandava CN, Furmanski LA, Strominger JL, Speck SH . (1991). Proc Natl Acad Sci USA 88: 3942–3946.

  • Wu DY, Kalpana GV, Goff SP, Schubach WH . (1996). J Virol 70: 6020–6028.

  • Yu C, Krystal G, Dent P, Grant S . (2002). Clin Cancer Res 8: 2976–2984.

  • Yue W, Davenport MG, Shackelford J, Pagano JS . (2004). J Virol 78: 3542–3552.

  • Yue W, Gershburg E, Pagano JS . (2005). J Virol 79: 5880–5885.

  • Zhou M, Halanski MA, Radonovich MF, Kashanchi F, Peng J, Price DH et al. (2000). Mol Cell Biol 20: 5077–5086.

  • Zhu Y, Pe'ery T, Peng J, Ramanathan Y, Marshall N, Marshall T et al. (1997). Genes Dev 11: 2622–2632.

  • Zimber-Strobl U, Strobl LJ, Meitinger C, Hinrichs R, Sakai T, Furukawa T et al. (1994). EMBO J 13: 4973–4982.

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Acknowledgements

We thank Martin Rowe for the gift of the PE2 antibody, Sasha Akoulitchev, Andrew Rice and Andy Bell for gifts of plasmids, Bettina Kempkes for the gift of the ER/EB2-5 cell line and Paul Lieberman for advice on ChIP assays. This work was supported by a Wellcome Trust Career Development Fellowship (064014) to MJW and a BBSRC studentship to SJBJ.

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  1. Department of Biochemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, UK

    S J Bark-Jones, H M Webb & M J West

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  1. S J Bark-Jones
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Correspondence to M J West.

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Bark-Jones, S., Webb, H. & West, M. EBV EBNA 2 stimulates CDK9-dependent transcription and RNA polymerase II phosphorylation on serine 5. Oncogene 25, 1775–1785 (2006). https://doi.org/10.1038/sj.onc.1209205

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