Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver

Abstract

The role of the hepatitis B virus protein HBx in liver cell proliferation and apoptosis remains controversial. Using a transgenic mouse model, we have recently shown that HBx stimulates the apoptotic turnover of hepatocytes, independently of p53. In this paper, we tested whether the proapoptotic function of HBx can interfere with Bcl-2 during hepatic apoptosis in vivo. HBx transgenic mice were crossed with PK-hBcl-2 mice that are protected against Fas killing by constitutive overexpression of Bcl-2 in hepatocytes. In a lethal challenge with Fas antibodies, HBx expressed at low levels restored sensitivity to Fas-mediated apoptosis and fulminant hepatic failure in mice overexpressing Bcl-2. Furthermore, cytochrome c release from mitochondria and caspase 3 activation were restored to normal levels in HBx/Bcl-2 mice during transduction of the Fas signal. Thus, the proapoptotic activity of HBx overcomes or bypasses the inhibitory effect of Bcl-2 against Fas cytotoxicity. This effect was not apparently mediated through downregulation of the PK-hBcl-2 transgene or via delocalization of the Bcl-2 protein, and a direct interaction of HBx with Bcl-2, Bcl-XL or Bax could not be evidenced in yeast two-hybrid assays. We further show that apoptosis induced by ectopic expression of HBx is associated with mitochondrial membrane alterations and caspase 3 activation. Our data indicate that the dominant function of HBx upon Bcl-2-regulated control of apoptosis might play an important role in the pathogenesis of chronic hepatitis B.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Adams JM, Cory S . 1998 Science 281: 1322–1326

  • Aillet F, Masutani H, Elbim C, Raoul H, Chene L, Nugeyre MT, Paya C, Barre-Sinoussi F, Gougerot-Pocidalo MA, Israel N . 1998 J. Virol. 72: 9698–9705

  • Amicone L, Spagnoli FM, Späth G, Giordano S, Tommasini C, Bernardini S, De Luca V, Della Rocca C, Weiss MC, Comoglio PM, Tripodi M . 1997 EMBO J. 16: 495–503

  • Balsano C, Billet O, Bennoun M, Cavard C, Zider A, Grimber G, Natoli G, Briand P, Levrero M . 1993 Arch. Virol. 8: 63–71

  • Beasley RP, Lin CC, Hwang LY, Chien CS . 1981 Lancet 2: 1129–1133

  • Benn J, Schneider RJ . 1995 Proc. Natl. Acad. Sci. USA 92: 11215–11219

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

  • Billet O, Grimber G, Levrero M, Seye KA, Briand P, Joulin V . 1995 J. Virol. 69: 5912–5916

  • Buendia MA . 1992 Adv. Cancer Res. 59: 167–226

  • Chinnaiyan AM, O'Rourke K, Tewari M, Dixit VM . 1995 Cell 81: 505–512

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

  • de la Coste A, Fabre M, McDonell N, Porteu A, Gilgenkrantz H, Perret C, Kahn A, Mignon A . 1999 Am. J. Physiol. 277: G702–G708

  • Desagher S, Osen-Sand A, Nichols A, Eskes R, Montessuit S, Lauper S, Maundrell K, Antonsson B, Martinou J-C . 1999 J. Cell. Biol. 144: 891–901

  • Diao J, Khine AA, Sarangi F, Hsu E, Iorio C, Tibbles LA, Woodgett JR, Penninger J, Richardson CD . 2001 J. Biol. Chem. 276: 8328–8340

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

  • Eskes R, Desagher S, Antonsson B, Martinou J-C . 2000 Mol. Cell. Biol. 20: 929–935

  • Feldmann G, Haouzi D, Moreau A, Durand-Schneider AM, Bringuier A, Berson A, Mansouri A, Fau D, Pessayre D . 2000 Hepatology 31: 674–683

  • Flajolet M, Rotondo G, Daviet L, Bergametti F, Inchauspe G, Tiollais P, Transy C, Legrain P . 2000 Gene 242: 369–379

  • Galibert F, Mandart E, Fitoussi F, Tiollais P, Charnay P . 1979 Nature 281: 646–650

  • Galle PR, Hofmann WJ, Walczak H, Schaller H, Otto G, Stremmel W, Krammer PH, Runkel L . 1995 J. Exp. Med. 182: 1223–1230

  • Grandgirard D, Studer E, Monney L, Belser T, Fellay I, Borner C, Michel MR . 1998 EMBO J. 17: 1268–1278

  • Grasl-Kraupp B, Ruttkay-Nedecky B, Mullauer L, Taper H, Huber W, Bursch W, Schulte-Hermann R . 1997 Hepatology 25: 906–912

  • Green DR, Reed JC . 1998 Science 281: 1309–1312

  • Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ . 1993 Cell 75: 805–816

  • Hollenberg SM, Sternglanz R, Cheng PF, Weintraub H . 1995 Mol. Cell. Biol. 15: 3813–3822

  • Juin P, Hueber AO, Littlewood T, Evan G . 1999 Genes Dev. 13: 1367–1381

  • 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

  • Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD . 1997 Science 275: 1132–1136

  • Kondo T, Suda T, Fukuyama H, Adachi M, Nagata S . 1997 Nat. Med. 3: 409–413

  • Lachronique V, Mignon A, Fabre M, Viollet B, Bouquet N, Molina T, Porteu A, Henrion A, Bouscary D, Varlet P, Joulin V, Kahn A . 1996 Nat. Med. 2: 80–86

  • Lara-Pezzi E, Armesilla AL, Majano PL, Redondo JM, Lopez-Cabrera M . 1998 EMBO J. 17: 7066–7077

  • Lecoeur H, Gougeon M-L . 1996 J. Immunol. Methods 198: 87–99

  • Lee DK, Park SH, Yi Y, Choi SG, Lee C, Parks WT, Cho H, de Caestecker MP, Shaul Y, Roberts AB, Kim SJ . 2001 Genes Dev. 15: 455–466

  • Lee T-H, Elledge SJ, Butel JS . 1995 J. Virol. 69: 1107–1114

  • Li H, Zhu H, Xu CJ, Yuan J . 1998 Cell 94: 491–501

  • Macho A, Decaudin D, Castedo M, Hirsch T, Susin SA, Zamzami N, Kroemer G . 1996 Cytometry 25: 333–340

  • Murphy KM, Streips UN, Lock RB . 1999 Oncogene 18: 5991–5999

  • Nagata S . 1997 Cell 88: 355–365

  • Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T, Nagata S . 1993 Nature 364: 806–809

  • Oguey D, Dumenco LL, Pierce RH, Fausto N . 1996 Hepatology 24: 1024–1033

  • Ojala PM, Yamamoto K, Castanos-Velez E, Biberfeld P, Korsmeyer SJ, Makela TP . 2000 Nat. Cell. Biol. 2: 819–825

  • Pan J, Duan LX, Sun BS, Feitelson MA . 2001 J. Gen. Virol. 82: 171–182

  • Petit PX, Lecoeur H, Zorn E, Dauguet C, Mignotte B, Gougeon M-L . 1995 J. Cell. Biol. 130: 157–167

  • Pollicino T, Terradillos O, Lecoeur H, Gougeon ML, Buendia MA . 1998 Biomed. Pharmacother. 52: 363–368

  • Rahmani Z, Huh KW, Lasher R, Siddiqui A . 2000 J. Virol. 74: 2840–2846

  • Rodriguez I, Matsuura K, Khatib K, Reed JC, Nagata S, Vassalli P . 1996 J. Exp. Med. 183: 1031–1036

  • Scaffidi C, Fulda S, Srinivasan A, Friesen C, Li F, Tomaselli KJ, Debatin K-M, Krammer PH, Peter ME . 1998 EMBO J. 17: 1675–1687

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

  • Shih WL, Kuo ML, Chuang SE, Cheng AL, Doong SL . 2000 J. Biol. Chem. 275: 25858–25864

  • 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, Israêl A, Kremsdorf D, Bréchot C . 1998 Oncogene 16: 2051–2063

  • Sitterlin D, Lee TH, Prigent S, Tiollais P, Butel JS, Transy C . 1997 J. Virol. 71: 6194–6199

  • Slagle BL, Lee TH, Medina D, Finegold MJ, Butel JS . 1996 Mol. Carcinogenesis 15: 261–269

  • Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang H-G, Reed JC, Nicholson DW, Alnemri ES, Green DR, Martin SJ . 1999 J. Cell. Biol. 144: 281–292

  • Spengler U, Zachoval R, Gallati H, Jung MC, Hoffmann R, Riethmuller G, Pape G . 1996 Cytokine 8: 864–872

  • Strand S, Hofmann WJ, Hug H, Muller M, Otto G, Strand D, Mariani SM, Stremmel W, Krammer PH, Galle PR . 1996 Nat. Med. 2: 1361–1366

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

  • Su F, Theodosis CN, Schneider RJ . 2001 J. Virol. 75: 215–225

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

  • Terradillos O, Billet O, Renard CA, Lévy R, Molina T, Briand P, Buendia MA . 1997 Oncogene 14: 395–404

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

  • Transy C, Legrain P . 1995 Mol. Biol. Rep. 21: 119–127

  • Twu JS, Schloemer RH . 1987 J. Virol. 61: 3448–3453

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

  • Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng T-I, Jones DP, Wang X . 1997 Science 275: 1129–1132

  • Yeh CT, Shen CH, Tai DI, Chu CM, Liaw YF . 2000 Oncogene 19: 5213–5220

  • Yen BTS . 1996 J. Biomed. Sci. 3: 20–30

  • Yin XM, Wang K, Gross A, Zhao Y, Zinkel S, Klocke B, Roth KA, Korsmeyer SJ . 1999 Nature 400: 886–891

Download references

Acknowledgements

We are grateful to Jean-Claude Martinou for stimulating discussions and critical review of the manuscript, and to Pierre Tiollais for his constant support. We thank Phil J Barr for plasmids pCMV-Bcl-2, pCMV-Bax and pCMV-Bcl-xL, and Catherine Transy for her support and advice in the yeast two-hybrid assays. We also thank Emmanuelle Perret for excellent assistance in confocal microscopy. O Terradillos was supported by fellowships from the Ligue Nationale pour la Recherche contre le Cancer and the Association pour la Recherche sur le Cancer (ARC). This work was supported in part by the ARC grant 9209.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marie-Annick Buendia.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Terradillos, O., de La Coste, A., Pollicino, T. et al. The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver. Oncogene 21, 377–386 (2002). https://doi.org/10.1038/sj.onc.1205110

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205110

Keywords

This article is cited by

Search

Quick links