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Hepatitis B virus X mutants derived from human hepatocellular carcinoma retain the ability to abrogate p53-induced apoptosis

Oncogene volume 20, pages 3620–3628 (2001)Cite this article

Abstract

Chronic hepatitis B virus (HBV) infection and the integration of its X gene (HBx) are closely associated with the development of hepatocellular carcinoma (HCC). The integrated HBx frequently is truncated or contains point mutations. Previous studies indicated that these HBx mutants have a diminished co-transactivational activity. We have compared the effects of wild-type (wt) HBx and its naturally occurring mutants derived from human HCCs on transcriptional co-transactivation, apoptosis and interactive effects with p53. We demonstrated that overexpression of mutant, but not wt HBx, is defective in transcriptional co-transactivation of the NF-κB-driven luciferase reporter. By using a microinjection technique, the HBx mutants were shown to have an attenuated pro-apoptotic activity. This deficiency may be attributed to multiple mutations in the co-transactivation domain of HBx, that leads to decreased stability of the translated product. However, wt or mutant HBx bind to p53 in vitro and retain their ability to block p53-mediated apoptosis in vivo, which has been implicated as its major tumor suppressor function. The abrogation of p53-mediated apoptosis by integrated HBx mutants may provide a selective clonal advantage for preneoplastic or neoplastic hepatocytes and contribute to hepatocellular carcinogenesis.

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References

  • Aguilar F, Harris CC, Sun T, Hollstein M, Cerutti P . 1994 Science 264: 1317–1319

  • Andrisani OM, Barnabas S . 1999 Int. J. Oncol. 15: 373–379

  • Arbuthnot P, Capovilla A, Kew MC . 2000 J. Gastroenterol. Hepatol. 15: 357–368

  • Avantaggiati M, Natoli G, Balsano C, Chirillo P, Artini M, Collepardo DD, Levrero M . 1993 Oncogene 8: 1567–1574

  • Baeurele PA, Baltimore D . 1996 Cell 87: 13–20

  • Baichwal VR, Baeuerle PA . 1997 Curr. Biol. 7: R94–R96

  • Baldwin JAS . 1996 Annu. Rev. Immunol. 14: 649–681

  • Beasley RP, Hwang LY, Lin CC, Chien CS . 1981 Lancet 2: 1129–1131

  • Becker SA, Lee TH, Butel JS, Slagle BL . 1998 J. Virol. 72: 266–272

  • Beg AA, Baltimore D . 1996 Science 274: 782–784

  • Bergametti F, Prigent S, Luber B, Benoit A, Tiollais P, Sarasin A, Transy C . 1999 Oncogene 18: 2860–2871

  • Bours V, Bentires-Alj M, Hellin A, Viatour P, Robe P, Delhalle S, Benoit V, Merville M . 2000 Biochem. Pharmacol. 60: 1085–1089

  • Brechot C, Gozuacik D, Murakami Y, Paterlini-Brechot P . 2000 Semin. Cancer Biol. 10: 211–231

  • Bressac B, Kew M, Wands J, Ozturk M . 1991 Nature 350: 429–431

  • Caselmann WH . 1995 J. Hepatol. 22: 1 Suppl 34–37

  • Chen WN, Oon CJ, Leong AL, Koh S, Teng SW . 2000 Biochem. Biophys. Res. Commun. 276: 885–892

  • Chirillo P, Pagano S, Natoli G, Puri PL, Burgio VL, Balsono C, Levrero M . 1997 Proc. Natl. Acad. Sci. USA 94: 8162–8167

  • Chirillo P, Falco M, Puri P, Artini M, Balsano C, Levrero M, Natoli G . 1996 J. Virol. 70: 641–646

  • Dandri M, Schirmacher P, Rogler C . 1996 J. Virol. 70: 5246–5254

  • Doitsh G, Shaul Y . 1999 Oncogene 18: 7506–7513

  • Dulic V, Kaufmann WK, Wilson SJ, Tisty TD, Lees E, Harper JW, Elledge SJ, Reed SI . 1994 Cell 76: 1013–1023

  • Dyson N, Howley PM, Munger K, Harlow E . 1989 Science 243: 934–937

  • Elmore LW, Hancock AR, Chang SF, Wang XW, Chang S, Callahan CP, Geller DA, Will H, Harris CC . 1997 Proc. Natl. Acad. Sci. USA 94: 14707–14712

  • Feitelson MA, Duan LX . 1997 Am. J. Pathol. 150: 1141–1157

  • Feitelson MA, Zhu M, Duan LX, London WT . 1993 Oncogene 8: 1109–1117

  • Good L, Sun S . 1996 J. Virol. 70: 2730–2735

  • Gottlob K, Pagano S, Levero M, Graessmann A . 1998 Cancer Res. 58: 3566–3570

  • Grimm S, Bauer MK, Baeuerle PA, Schulze-Osthoff K . 1996 J. Cell Biol. 134: 13–23

  • Hettmann T, DiDonato J, Karin M, Leiden JM . 1999 J. Exp. Med. 189: 145–158

  • Herrero J, Mathew P, Paya C . 1995 J. Virol. 69: 2168–2174

  • Hirai H, Suzuki T, Fujisawa J, Inoue J, Yoshida M . 1994 Proc. Natl. Acad. Sci. USA 91: 3584–3588

  • Hohne M, Schaefer S, Seifer M, Feitelson MA, Paul D, Gerlich WH . 1990 EMBO J. 9: 1137–1145

  • Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC . 1991 Nature 350: 427–428

  • Hu KQ, Vierling JM, Siddiqui A . 1990 Proc. Natl. Acad. Sci. USA 87: 7140–7147

  • Huang Y, Johnson KR, Norris JS, Fan W . 2000 Cancer Res. 60: 4426–4432

  • Jia L, Wang XW, Harris CC . 1999 Int. J. Cancer 80: 875–879

  • Kaltschmidt B, Kalschmidt C, Hofmann TG, Hehner SP, Droge W, Schmits ML . 2000 Eur. J. Biochem. 267: 3828–3835

  • Kew MC . 1996 Clin. Lab. Med. 16: 395–406

  • Kew MC . 1997 Hepatology 25: 1037–1038

  • Kim CM, Koike K, Saito I, Miyamura T, Jay G . 1991 Nature 351: 317–320

  • Kim H, Lee H, Yun Y . 1998 J. Biol. Chem. 273: 381–385

  • Lacoste J, Petropoulos L, Pepin N, Hiscott J . 1995 J. Virol. 69: 564–569

  • Lane D . 1992 Nature 358: 15–16

  • Lane D, Crawford LV . 1979 Nature 278: 261–263

  • Lee SG, Rho HM . 2000 Oncogene 19: 468–471

  • Levine AJ . 1997 Cell 88: 323–331

  • Linzer DI, Levine AJ . 1979 Cell 17: 43–52

  • Lin Y, Nomura T, Yamashita T, Dorjsuren D, Tang H, Murakami S . 1997 Cancer Res. 57: 5137–5142

  • Liu ZG, Hsu H, Goeddel DV, Karin M . 1996 Cell 87: 565–576

  • Lowe SW, Bodis S, McClatchey A, Remington L, Ruley HE, Fisher DE, Housman DE, Jacks T . 1994 Science 260: 807–810

  • Lowe SW, Ruley HE, Jacks T, Housman DE . 1993 Cell 74: 957–967

  • Mahe Y, Mukaida N, Kuno K, Akiyama M, Ikeda N, Matsushima K, Murakami S . 1991 J. Biol. Chem. 266: 13759–13763

  • Murakami S . 1999 Intervirology 42: 81–99

  • Oren M . 1999 J. Biol. Chem. 274: 36031–36034

  • Ogden SK, Lee KC, Barton MC . 2000 J. Biol. Chem. 275: 27806–27814

  • Park US, Park SK, Lee YI, Park JG, Lee YI . 2000 Oncogene 19: 3384–3394

  • Paterlini P, Poussin K, Kew M, Franco D, Brechot C . 1995 Hepatology 21: 313–321

  • Poussin K, Dienes H, Sirma H, Urban S, Beaugrand M, Franco D, Schirmacher P, Brechot C, Brechot PP . 1999 Int. J. Cancer 80: 497–505

  • Prives C . 1993 Curr. Opin. Cell. Biol. 5: 214–218

  • Sarnow P, Ho YS, Williams J, Levine AJ . 1982 Cell 28: 387–394

  • Schuster R, Gerlich WH, Schaefer S . 2000 Oncogene 19: 1173–1180

  • Schwartz D, Rotter V . 1998 Semin. Cancer Biol. 8: 325–336

  • Seifer M, Hohne M, Schaefer S, Gerlich WH . 1991 J. Hepatol. 13: Suppl. 4 S61–S65

  • Shirakata Y, Kawada M, Fujiki Y, Sano H, Oda M, Yaginuma K, Kobayashi M, Koike K . 1989 Jpn. J. Cancer Res. 80: 617–621

  • Sirma H, Giannini C, Poussin K, Paterlini P, Kremsdorf D, Brechot C . 1999 Oncogene 18: 4848–4859

  • Sirma H, Weil R, Rosmorduc O, Urban S, Israel A, Kremsdorf D, Brechot C . 1998 Oncogene 16: 2051–2063

  • Sohn S, Jaitovitch-Groisman I, Benlimame N, Galipeau J, Batist G, Alaoui-Jamali MA . 2000 Mutat. Res. 460: 17–28

  • Speir E, Modali R, Huang ES, Leon MB, Shawl F, Finkel T, Epstein SE . 1994 Science 265: 391–394

  • Su F, Schneider RJ . 1997 Proc. Natl. Acad. Sci. USA 94: 8744–8749

  • Su F, Schneider R . 1996 J. Virol. 70: 4558–4566

  • Su Q, Schroder CH, Hofmann WJ, Otto G, Pichlmayr R, Bannasch P . 1998 Hepatology 27: 1109–1120

  • Su Q, Schroder CH, Otto G, Bannasch P . 2000 Mutat. Res. 462: 365–380

  • Sun S, Elwood J, Beraud C, Greene W . 1994 Mol. Cell. Biol. 14: 7377–7384

  • Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe SW, Jacks T, Van Dyke T . 1994 Cell 78: 703–711

  • Szekely L, Selivanova G, Magnusson KP, Klein G, Wiman KG . 1993 Proc. Natl. Acad. Sci. USA 90: 5455–5459

  • Takada S, Shirakata Y, Kaneniwa N, Koike K . 1999 Oncogene 18: 6965–6973

  • Terradillos O, Pollicino T, Lecoeur H, Tripodi M, Gougeon ML, Tiollais P, Buendia MA . 1998 Oncogene 17: 2115–2123

  • Truant R, Antunovic J, Greenblatt J, Prives C, Cromlish JA . 1995 J. Virol. 69: 1851–1859

  • Twu JS, Lai MY, Chen DS, Robinson WS . 1993 Virology 192: 346–350

  • Ueda H, Ullrich SJ, Gangemi JD, Kappel CA, Ngo L, Feitelson MA, Jay G . 1995 Nat. Genet. 9: 41–47

  • Unger T, Shaul Y . 1990 EMBO J. 9: 1889–1895

  • Unsal H, Yakicier C, Marcais C, Kew M, Volkmann M, Zentgraf H, Isselbacher KJ, Ozturk M . 1994 Proc. Natl. Acad. Sci. USA 91: 822–826

  • Van Antwerp DJ, Martin SJ, Kafri T, Green DR, Verma IM . 1996 Science 274: 787–789

  • Wang CY, Mayo MW, Baldwin AS . 1996 Science 274: 784–787

  • Wang XW . 1999 Anticancer Res. 19: 4759–4771

  • Wang XW, Harris CC . 1997 J. Cell. Physiol. 173: 247–255

  • Wang XW, Vermeulen W, Coursen JD, Gibson M, Lupold SE, Forrester K, Xu G, Elmore L, Yeh H, Hoeijmarkers JH, Harris CC . 1996 Genes Dev. 10: 1219–1232

  • Wang XW, Gibson MK, Vermeulen W, Yeh H, Forrester K, Sturzbecher HW, Hoeijmakers JHJ, Harris CC . 1995 Cancer Res. 55: 6012–6016

  • Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC . 1994 Proc. Natl. Acad. Sci. USA 91: 2230–2234

  • Wu X, Levine AJ . 1994 Proc. Natl. Acad. Sci. USA 91: 23602–23606

  • Yu DY, Moon HB, Son JK, Jeong S, Yu SL, Yoon H, Han YM, Lee CS, Park JS, Lee CH, Hyun BH, Murakami S, Lee KK . 1999 J. Hepatol. 31: 123–132

  • Yun C, Lee J, Park H, Jin Y, Park S, Park K, Cho H . 2000 Oncogene 19: 5163–5172

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Acknowledgements

The authors thank B Vogelstein, J Yuan, and J Brady for providing the plasmids, and Ms D Dudek for editorial assistance.

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Authors and Affiliations

  1. Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, Maryland, USA

    Teh-Ia Huo, Xin W Wang, Marshonna Forgues, Chuan-Ging Wu, Elisa A Spillare & Curtis C Harris

  2. Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taiwan

    Teh-Ia Huo

  3. Necker Institute, Paris, France

    Carlo Giannini & Christian Brechot

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Huo, TI., Wang, X., Forgues, M. et al. Hepatitis B virus X mutants derived from human hepatocellular carcinoma retain the ability to abrogate p53-induced apoptosis. Oncogene 20, 3620–3628 (2001). https://doi.org/10.1038/sj.onc.1204495

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