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Hepatitis B Virus X Protein: Structure-Function Relationships and Role in Viral Pathogenesis

  • Chapter
Transcription Factors

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 166))

Abstract

The hepatitis B virus (HBV) genome codes for a 16.5-KDa protein termed pX or HBx which is a prevalent marker in the liver of patients with hepatit is B-associated hepatocellular carcinoma (HCC). Although the specific function of HBx in natural infection remains elusive, it is considered to play an important role in the etiology of HBV-induced HCC. It is a multifunctional regulatory protein that is best characterized as promiscuous transactivator. It can induce different signaling pathways, deregulate cell cycle checkpoint s or even adapt cell responses to genotoxic stress and protein degradation. The oncogenic nature of HBx is evident from its ability to transform permanent cell lines ex vivo and induce liver-specific tumors in transgenic animals. RNA interference against the expression of HBx could be an effective therapeutic tool in the management of hepatitis B-associated liver diseases.

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References

  • Ahn JY, Jung EY, Kwun HJ, Lee CW, Sung YC, Jang KL (2002) Dual effects of hepatitis B virus X protein on the regulation of cell-cycle control depending on the status of cellular p53. J Gen Virol 83:2765–2772

    PubMed  CAS  Google Scholar 

  • Amaro MJ, Bartolome J, Carreno V (1999) Hepatitis B virus X protein transactivates the inducible nitric oxide synthase promoter. Hepatology 29:915–923

    Article  PubMed  CAS  Google Scholar 

  • Antunovic J, Lemieux N, Cromlish JA (1993) The 17 kDa HBx protein encoded by hepatitis Bvirus interacts with the activation domains of Oct-1, and functions as a coactivator in the activation and repression of a human U6 promoter. Cell Mol Biol Res 39:463–482

    PubMed  CAS  Google Scholar 

  • Arbuthnot P, Capovilla A, Kew M (2000) Putative role of hepatitis B virus X protein in hepatocarcinogenesis: effects on apoptosis, DNA repair, mitogen-activated protein kinase and JAK/STAT pathways. J Gastroenterol Hepatol 15:357–368

    Article  PubMed  CAS  Google Scholar 

  • Arima T, Nakao K, Nakata K, Ishikawa H, Ichikawa T, Hamasaki K, Ishii N, Eguchi K (2002) Transactivation of human alpha-fetoprotein gene by X-gene product of hepatitis Bvirus in human hepatoma cells. Int J Mol Med 9:397–400

    PubMed  CAS  Google Scholar 

  • Assogba BD, Choi BH, Rho HM (2002) Transcriptional activation of the promoter of human cytomegalovirus immediate early gene (CMV-IE) by the hepatitis B viral X protein (HBx) through the NF-kappaB site. Virus Res 84:171–179

    Article  PubMed  CAS  Google Scholar 

  • Aufiero B, Schneider RJ (1990) The hepatitis B virus X-gene product trans-activates both RNA polymerase II and III promoters. EMBO J 9:497–504

    PubMed  CAS  Google Scholar 

  • Avantaggiati ML, Natoli G, Balsano C, Chirillo P, Artini M, De Marzio E, Collepardo D, Levrero M (1993) The hepatitis B virus (HBV) pX transactivates the c-fos promoter through multiple cis-acting elements. Oncogene 8:1567–1574

    PubMed  CAS  Google Scholar 

  • Balsano C, Avantaggiati ML, Natoli G, De Marzio E, Will H, Perricaudet M, Levrero M (1991) Full-length and truncated versions of the hepatitis B virus (HBV) X protein (pX) transactivate the c-myc protooncogene at the transcriptional level. Biochem Biophys Res Commun 176:985–992

    Article  PubMed  CAS  Google Scholar 

  • Barnabas S, Hai T, Andrisani OM (1997) The hepatitis B virus X protein enhances the DNA binding potential and transcription efficacy of blip transcription factors. J Biol Chem 272:20684–20690

    Article  PubMed  CAS  Google Scholar 

  • Barnabas S, Andrisani OM (2000) Different regions of hepatitis B virus X protein are required for enhancement of blip-mediated transactivation versus transrepression. J Virol 74:83–90

    Article  PubMed  CAS  Google Scholar 

  • Becker SA, Lee TH, Butel JS, Slagle BL (1998) Hepatitis B virus X protein interferes with cellular DNA repair. J Virol 72:266–272

    PubMed  CAS  Google Scholar 

  • Benn J, Schneider RJ (1994) Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. Proc Natl Acad Sci USA 91:10350–10354

    Article  PubMed  CAS  Google Scholar 

  • Benn J, Su F, Doria M, Schneider RJ (1996) Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal-regulated and c-Jun N-terminal mitogen-activated protein kinases. J Virol 70:4978–4985

    PubMed  CAS  Google Scholar 

  • Blum HE, Zhang ZS, Galun E, von Weizsacker F, Garner B, Liang TJ, Wands JR (1992) Hepatitis B virus X protein is not central to the viral life cycle in vitro. J Virol 66: 1223–1227

    PubMed  CAS  Google Scholar 

  • Bouchard MJ, Wang LH, Schneider RJ (2001a) Calcium signaling by HBx protein in hepatitis B virus DNA replication. Science 294:2376–2378

    Article  PubMed  CAS  Google Scholar 

  • Bouchard M, Giannakopoulos S, Wang EH, Tanese N, Schneider RJ (200lb) Hepatitis B virus HBx protein activation of cyclin A-cyclin-dependent kinase 2 complexes and G1 transit via a Src kinase pathway. J Virol 75:4247–4257

    Article  Google Scholar 

  • Bouchard MJ, Puro RJ, Wang L, Schneider RJ (2003) Activation and inhibition of cellular calcium and tyrosine kinase signaling pathways identify targets of the HBx protein involved in hepatitis B virus replication. J Virol 77:7713–7719

    Article  PubMed  CAS  Google Scholar 

  • Bressac B, Kew M, Wands J, Ozturk M (1991) Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350:429–431

    Article  PubMed  CAS  Google Scholar 

  • Carretero M, Gomez-Gonzalo M, Lara-Pezzi E, Benedicto I, Aramburu J, Martinez-Martinez S, Redondo J, Lopez-Cabrera M (2002) The hepatitis B virus X protein binds to and activates the NH(2)-terminal trans-activation domain of nuclear factor of activated T cells-1. Virology 299:288–300

    Article  PubMed  CAS  Google Scholar 

  • Caselmann WH (1995) Transactivation of cellular gene expression by hepatitis B viral proteins: a possible molecular mechanism of hepatocarcinogenesis. J Hepatol 22 (1 Suppl): 34–37

    PubMed  CAS  Google Scholar 

  • Caselmann WH (1996) Trans-activation of cellular genes by hepatitis B virus proteins: a possible mechanism of hepatocarcinogenesis. Adv Virus Res 47:253–302

    Article  PubMed  CAS  Google Scholar 

  • Chen HS, Kaneko S, Girones R, Anderson RW, Hornbuckle WE, Tennant BC, Cote PJ, Gerin JL, Purcell RH, Miller RH (1993) The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. J Virol 67:1218–1226

    PubMed  CAS  Google Scholar 

  • Cheong JH, Yi M, Lin Y, Murakami S (1995) Human RPB5, a subunit shared by eukaryotic-nuclear RNA polymerases, binds human hepatitis B virus X protein and may play a role in X transactivation. EMBO J 14:143–150

    PubMed  CAS  Google Scholar 

  • Chirillo P, Falco M, Puri PL, Artini M, Balsano C, Levrero M, Natoli G. (1996) Hepatitis B virus pX activates NF-kappa B-dependent transcription through a Raf-independent pathway. J Virol 70:641–646

    PubMed  CAS  Google Scholar 

  • Chirillo P, Pagano S, Natoli G, Puri PL, Burgio VL, Balsano C, Levrero M (1997) The hepatitis B virus X gene induces p53-mediated programmed cell death. Proc Natl Acad Sci USA 94:8162–8167

    Article  PubMed  CAS  Google Scholar 

  • Choi BH, Park GT, Rho HM (1999) Interaction of hepatitis B viral X protein and CCAAT/enhancer-binding protein alpha synergistically activates the hepatitis B viral enhancer II/pregenomic promoter. J Biol Chem 274:2858–2865

    Article  PubMed  CAS  Google Scholar 

  • Colgrove R, Simon G, Ganem D (1989) Transcriptional activation of homologous and heterologous genes by the hepatitis B virus X gene product in cells permissive for viral replication. J Virol 63:4019–4026

    PubMed  CAS  Google Scholar 

  • Cressman DE, Diamond RH, Taub R (1995) Rapid activation of the Stats transcription complex in liver regeneration. Hepatology 21:1443–1449

    Article  PubMed  CAS  Google Scholar 

  • Cromlish JA (1996) Hepatitis B virus-induced hepatocellular carcinoma: possible roles for HBx. Trends Microbiol 4:270–274

    Article  PubMed  CAS  Google Scholar 

  • Cross JC, Wen P, Rutter WJ (1993) Transactivation by hepatitis B virus X protein is promiscuous and dependent on mitogen-activated cellular serine/threonine kinases. Proc Natl Acad Sci USA 90:8078–8082

    Article  PubMed  CAS  Google Scholar 

  • de-Medina T, Shaul Y (1994) Functional and structural similarity between the X protein of hepatitis B virus and nucleoside diphosphate kinases. FEBS Lett 351:423–426

    Article  Google Scholar 

  • de-Medina T, Haviv I, Noiman S, Shaul Y (1994) The X protein of hepatitis B virus has a ribo/deoxy ATPase activity. Virology 202:401–407

    Article  Google Scholar 

  • Doong SL, Lin MH, Tsai MM, Li TR, Chuang SE, Cheng AL (1998) Transactivation of the human MDRI gene by hepatitis B virus X gene product. J Hepatol 29:872–878

    Article  PubMed  CAS  Google Scholar 

  • Dopheide TA, Azad AA (1996) The hepatitis B virus X protein is a potent AMP kinase. J Gen Virol 77:173–176

    Article  PubMed  CAS  Google Scholar 

  • Elmore LW, Hancock AR, Chang SF, Wang XW, Chang S, Callahan CP, Geller DA, Will H, Harris CC (1997) Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. Proc Natl Acad Sci USA 94:14707–4712

    Article  PubMed  CAS  Google Scholar 

  • Farshid M, Nedjar S, Mitchell F, Biswas R (1997) Effect of hepatitis B virus X protein on the expression of retinoblastoma gene product. Acta Virol 41:125–129

    PubMed  CAS  Google Scholar 

  • Flajolet M, Gegonne A, Ghysdael J, Tiollais P, Buendia MA, Fourel G (1997) Cellular and viral tr ans-acting factors modulate N-myc2 promoter activity in woodchuck liver tumors. Oncogene 15:1103–1110

    Article  PubMed  CAS  Google Scholar 

  • Forgues M, Difilippantonio MJ, Linke SP, Ried T, Nagashima K, Feden J, Valerie K, Fukasawa K, Wang XW (2003) Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles. Mol Cell Biol 23:5282–5292

    Article  PubMed  CAS  Google Scholar 

  • Galibert F, Mandart E, Fitoussi F, Tiollais P, Charnay P (1979) Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli. Nature 281:646–650

    Article  PubMed  CAS  Google Scholar 

  • Galibert F, Chen TN, Mandart E (1982) Nucleotide sequence of a cloned woodchuck hepatitis virus genome: comparison with the hepatitis B virus sequence. J Virol 41:51–65

    PubMed  CAS  Google Scholar 

  • Ganem D, Schneider RJ (2001) Hepadnaviridae: The viruses and their replication. In: Knipe DM, Howley PM (eds) Fields Virology (4th edn). Lippincott Williams and Wilkins, Philadephia, pp 2923–2969

    Google Scholar 

  • Gonzalez-Amaro R, Garcia-Monzon C, Garcia-Buey L, Moreno-Otero R, Alonso JL, Yague E, Pivel JP, Lopez-Cabrera M, Fernandez-Ruiz E, Sanchez-Madrid F. (1994) Induction of tumor necrosis factor alpha production by human hepatocytes in chronic viral hepatitis. J Exp Med 179:841–848.

    Article  PubMed  CAS  Google Scholar 

  • Goto T, Kato N, Yoshida H, Otsuka M, Moriyama M, Shiratori Y, Koike K, Matsumura M, Omata M (2003) Synergistic activation of the serum response element-dependent pathway by hepatitis B virus x protein and large-isoform hepatitis delta antigen. J Infect Dis 187:820–828

    Article  PubMed  CAS  Google Scholar 

  • Gottlob K, Fulco M, Levrero M, Graessmann A (1998a) The hepatitis B virus HBx protein inhibits caspase-3 activity. J Biol Chem 273:33347–33353

    Article  PubMed  CAS  Google Scholar 

  • Gottlob K, Pagano S, Levrero M, Graessmann A (1998b) Hepatitis B virus X protein transcription activation domains are neither required nor sufficient for cell transformation. Cancer Res 58:3566–3570

    PubMed  CAS  Google Scholar 

  • Groisman IJ, Koshy R, Henkler F, Groopman JD, Alaoui-Jamali MA (1999) Downregulation of DNA excision repair by the hepatitis B virus-x protein occurs in p53-proficient and p53-deficient cells. Carcinogenesis 20:479–483

    Article  PubMed  CAS  Google Scholar 

  • Guo WT, Wang J, Tam G, Yen TS, Ou JS (1991) Leaky transcription termination produces larger and smaller than genome size hepatitis B virus X gene transcripts. Virology 181:630–636

    Article  PubMed  CAS  Google Scholar 

  • Gupta A, Mal TK, Jayasuryan N, Chauhan VS (1995) Assignment of disulphide bonds in the X protein (HBx) of hepatitis B virus. Biochem Biophys Res Commun 212:919–924

    Article  PubMed  CAS  Google Scholar 

  • Haviv I, Vaizel D, Shaul Y (1996) pX, the HBV-encoded coactivator, interacts with components of the transcription machinery and stimulates transcription in a TAF-independent manner. EMBO J 15:3413–3420

    PubMed  CAS  Google Scholar 

  • Haviv I, Shamay M, Doitch G, Shaul Y (1998) Hepatitis B virus pX targets TFIIB in transcription coactivation. Mol Cell Biol 18:1562–1569

    PubMed  CAS  Google Scholar 

  • Hazzalin CA, Mahadevan LC (2002) MAPK-regulated transcription: a continuously variable gene switch? Nat Rev Mol Cell Biol 3:30–40

    Article  PubMed  CAS  Google Scholar 

  • Henkler F, Lopes AR, Jones M, Koshy R (1998) Erk-independent partial activation of AP-1 sites by the hepatitis B virus HBx protein. J Gen Virol 79:2737–2742

    PubMed  CAS  Google Scholar 

  • Hoare J, Henkler F, Dowling JJ, Errington W, Goldin RD, Fish D, McGarvey MJ (2001) Subcellular localisation of the X protein in HBV infected hepatocytes. J Med Virol 64:419–426

    Article  PubMed  CAS  Google Scholar 

  • Hohne M, Schaefer S, Seifer M, Feitelson MA, Paul D, Gerlich WH (1990) Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA. EMBO J 9:1137–1145

    PubMed  CAS  Google Scholar 

  • Hsu DK, Dowling CA, Jeng KC, Chen JT, Yang RY, Liu FT (1999) Galectin-3 expression is induced in cirrhotic liver and hepatocellular carcinoma. Int J Cancer 81:519–526

    Article  PubMed  CAS  Google Scholar 

  • Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC (1991) Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350:427–428

    Article  PubMed  CAS  Google Scholar 

  • Hu KQ, Yu CH, Vierling JM (1992) Up-regulation of intercellular adhesion molecule 1 transcription by hepatitis B virus X protein. Proc Natl Acad Sci USA 89:11441–11445

    Article  PubMed  CAS  Google Scholar 

  • Hu Z, Zhang Z, Doo E, Coux O, Goldberg AL, Liang TJ (1999) Hepatitis B virus X protein is both a substrate and a potential inhibitor of the proteasorne complex. J Virol 73:7231–7240

    PubMed  CAS  Google Scholar 

  • Hung L, Kumar V (2004) Specific inhibition of gene expression and transactivation functions of hepatitis B virus X protein and c-myc by small interfering RNAs. FEBS Lett 560:210–214

    Article  PubMed  CAS  Google Scholar 

  • Huo TI, Wang XW, Forgues M, Wu CG, Spillare EA, Giannini C, Brechot C, Harris CC (2001) Hepatitis B virus X mutants derived from human hepatocellular carcinoma retain the ability to abrogate p53-induced apoptosis. Oncogene 20:3620–3628

    Article  PubMed  CAS  Google Scholar 

  • Jaitovich-Groisman I, Benlimame n, Slagle BL, Perez MH, Alpert L, Song DJ, Fotouhi-Ardakani N, Galipeau J, Alaoui-Jamali MA (2001) Transcriptional regulation of the TFIIH transcription repair components XPB and XPD by the hepatitis B virus X protein in liver cells and transgenic liver tissue. J Biol Chem 276:14124–14132

    PubMed  CAS  Google Scholar 

  • Jameel S, Siddiqui A, Maguire HF, Rao KV (1990) Hepatitis B virus X protein produced in Escherichia coli is biologically functional. J Virol 64:3963–3966

    PubMed  CAS  Google Scholar 

  • Jia L, Wang XW, Harris CC (1999) Hepatitis B virus X protein inhibits nucleotide excision repair. Int J Cancer 80:875–879

    Article  PubMed  CAS  Google Scholar 

  • Jung EY, Kang HK, Chang J, Yu DY, Jang KL (2003) Cooperative transformation of murine fibroblast NIH3T3 cells by hepatitis C virus core protein and hepatitis B virus X protein. Virus Res 94:79–84

    Article  PubMed  CAS  Google Scholar 

  • Kang-Park S, Lee JH, Shin JH, Lee YI (2001) Activation of the IGF-II gene by HBV-X protein requires PKC and p44/p42 map kinase signalings. Biochem Biophys Res Commun 283:303–307

    Article  PubMed  CAS  Google Scholar 

  • Kay A, Mandart E, Trepo C, Galibert F (1985) The HBV HBX gene expressed in E. coli is recognised by sera from hepatitis patients. EMBO J 4:1287–1292

    PubMed  CAS  Google Scholar 

  • Kekule AS, Lauer U, Weiss L, Luber B, Hofschneider PH (1993) Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature 361:742–745

    Article  PubMed  CAS  Google Scholar 

  • Kidd-Ljunggren K, Oberg M, Kidd AH (1995) The hepatitis B virus X gene: analysis of functional domain variation and gene phylogeny using multiple sequences. J Gen Virol 76:2119–2130

    Article  PubMed  CAS  Google Scholar 

  • Kim CM, Koike K, Saito I, Miyamura T, Jay G (1991) HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351:317–320

    Article  PubMed  CAS  Google Scholar 

  • Kim H, Lee H, Yun Y (1998) X-gene product of hepatitis B virus induces apoptosis in liver cells. J Biol Chem 273:381–385

    Article  PubMed  CAS  Google Scholar 

  • Kim H, Lee YH, Won J, Yun Y (2001) Through induction of juxtaposition and tyrosine kinase activity of Jak1, X-gene product of hepatitis B virus stimulates Ras and the transcriptional activation through AP-1, NF-kappaB, and SRE enhancers. Biochem Biophys Res Commun 286:886–894

    Article  PubMed  CAS  Google Scholar 

  • Kim JH, Rho HM (2002). Activation of the human transforming growth factor alpha (TGF-alpha) gene by hepatitis B viral X protein (HBx) through AP-2 sites. Mol Cell Biochem 231:155–161

    Article  PubMed  CAS  Google Scholar 

  • Kim KH, Seong BL (2003) Pro-apoptotic function of HBV X protein is mediated by interaction with c-FLIP and enhancement of death-inducing signal. EMBO J 22:2104–2116

    Article  PubMed  CAS  Google Scholar 

  • Kim SO, Park JG, Lee YI (1996) Increased expression of the insulin-like growth factor I (IGF-I) receptor gene in hepatocellular carcinoma cell lines: implications of IGF-I receptor gene activation by hepatitis B virus X gene product. Cancer Res 56:3831–3836

    PubMed  CAS  Google Scholar 

  • Kim YC, Song KS, Yoon G, Nam MJ, Ryu WS (2001) Activated ras oncogene collaborates with HBx gene of hepatitis B virus to transform cells by suppressing HBx-mediated apoptosis. Oncogene 20:16–23

    Article  PubMed  CAS  Google Scholar 

  • Kim YK, Junn E, Park I, Lee Y, Kang C, Ahn JK (1999) Repression of hepatitis B virus X gene expression by hammerhead ribozymes. Biochem Biophys Res Commun 257: 759–765

    Article  PubMed  CAS  Google Scholar 

  • Klein NP, Schneider RJ (1997) Activation of Src family kinases by hepatitis B virus HBx protein and coupled signaling to Ras. Mol Cell Biol. 17:6427–6436

    PubMed  CAS  Google Scholar 

  • Klein NP, Bouchard MJ, Wang LH, Kobarg C, Schneider RJ (1999) Src kinases involved in hepatitis B virus replication. EMBO J 18:5019–5027

    Article  PubMed  CAS  Google Scholar 

  • Koike K, Moriya K, Yotsuyanagi H, Iino S, Kurokawa K (1994a) Induction of cell cycle progression by hepatitis B virus HBx gene expression in quiescent mouse fibroblasts. J Clin Invest 94:44–49

    Article  PubMed  CAS  Google Scholar 

  • Koike K, Moriya K, Iino S, Yotsuyanagi H, Endo Y, Miyamura T, Kurokawa K (1994b) High-level expression of hepatitis B virus HBx gene and hepatocarcinogenesis in transgenic mice. Hepatology 19:810–819

    Article  PubMed  CAS  Google Scholar 

  • Kong HJ, Hong SH, Lee MY, Kim HD, Lee JW, Cheong J (2000) Direct binding of hepatitis B virus X protein and retinoid X receptor contributes to phosphoenolpyruvate carboxykinase gene transactivation. FEBS Lett 483:114–118

    Article  PubMed  CAS  Google Scholar 

  • Kumar V, Jayasuryan N, Kumar R (1996) A truncated mutant (residues 58–140) of the hepatitis B virus X protein retains transactivation function. Proc Natl Acad Sci USA 93:5647–5652

    Article  PubMed  CAS  Google Scholar 

  • Kumar V, Singh M, Totey SM, Anand RK (2001) Bicistronic DNA construct comprising X-myc transgene for use in production of transgenic animal model systems for human hepatocellular carcinoma and transgenic animal model systems so produced. US Patent No. 6,274,788 B1

    Google Scholar 

  • Kwee L, Lucito R, Aufiero B, Schneider RJ (1992) Alternate translation initiation on hepatitis B virus X mRNA produces multiple polypeptides that differentially transactivate class II and III promoters. J Virol 66:4382–4389

    PubMed  CAS  Google Scholar 

  • Lakhtakia R, Kumar V, Reddi H, Mathur M, Dattagupta S, Panda SK (2003) Hepatocellular carcinoma in a hepatitis B ‘x’ transgenic mouse model: A sequential pathological evaluation. J Gastroenterol Hepatol 18:80–91

    Article  PubMed  Google Scholar 

  • Lara-Pezzi E, Armesilla AL, Majano PL, Redondo JM, Lopez-Cabrera M (1998) The hepatitis B virus X protein activates nuclear factor of activated T cells (NF-AT) by a cyclosporin A-sensitive pathway. EMBO J 17:7066–7077

    Article  PubMed  CAS  Google Scholar 

  • Lara-Pezzi E, Majano PL, Yanez-Mo M, Gomez-Gonzalo M, Carretero M, Moreno-Otero R, Sanchez-Madrid F, Lopez-Cabrera M (2001) Effect of the hepatitis B virus HBx protein on integrin-mediated adhesion to and migration on extracellular matrix. J Hepatol 34:409–415

    Article  PubMed  CAS  Google Scholar 

  • Lara-Pezzi E, Gornez-Gaviro MV, Galvez BG, Mira E, Iniguez MA, Fresno M, Martinez-A C, Arroyo AG, Lopez-Cabrera M (2002) The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression. J Clin Invest 110:1831–1838

    PubMed  CAS  Google Scholar 

  • Leach JK, Qiao L, Fang Y, Han SL, Gilfor D, Fisher PB, Grant S, Hylemon PB, Peterson D, Dent P (2003) Regulation of p21 and p27 expression by the hepatitis B virus X protein and the alternate initiation site X proteins, AUG2 and AUG3. J Gastroenterol Hepatol 18:376–385

    Article  PubMed  CAS  Google Scholar 

  • Lee MO, Kang HJ, Cho H, Shin EC, Park JH, Kim SJ (2001) Hepatitis B virus X protein induced expression of the Nur77 gene. Biochem Biophys Res Commun 288:1162–1168

    Article  PubMed  CAS  Google Scholar 

  • Lee S, Tarn C, Wang WH, Chen S, Hullinger RL, Andrisani OM (2002) Hepatitis B virus X protein differentially regulates cell cycle progression in X-transforming versus nontransforming hepatocyte (AML12) cell lines. J Biol Chem 277:8730–8740

    Article  PubMed  CAS  Google Scholar 

  • Lee SG, Rho HM (2000) Transcriptional repression of the human p53 gene by hepatitis B viral X protein. Oncogene 19:468–471

    Article  PubMed  CAS  Google Scholar 

  • Lee TH, Finegold MJ, Shen RF, DeMayo JL, Woo SL, Butel JS (1990) Hepatitis B virus transactivator X protein is not tumorigenic in transgenic mice. J Virol 64:5939–5947

    PubMed  CAS  Google Scholar 

  • Lee Y, Park US, Choi I, Yoon SK, Park YM, Lee YI (1998) Human interleukin 6 gene is activated by hepatitis B virus-X protein in human hepatoma cells. Clin Cancer Res 4:1711–1717

    PubMed  CAS  Google Scholar 

  • Lee YH, Yun Y (1998) HBx protein of hepatitis B virus activates Jak1-STAT signaling. J Biol Chem 273:25510–25515

    Article  PubMed  CAS  Google Scholar 

  • Lee YI, Lee S, Lee Y, Bong YS, Hyun SW, Yoo YD, Kim SJ, Kim YW, Poo HR (1998) The human hepatitis B virus transactivator X gene product regulates Sp1 mediated transcription of an insulin-like growth factor 11 promoter 4. Oncogene 16:2367–2380

    Article  PubMed  CAS  Google Scholar 

  • Lee YI, Kim SO, Kwon HJ, Park JG, Sohn MJ, Jeong SS (2001a) Phosphorylation of purified recombinant hepatitis B virus-X protein by mitogen-activated protein kinase and protein kinase C in vitro. J Virol Methods 95:1–10

    Article  PubMed  CAS  Google Scholar 

  • Lee YI, Kang-Park S, Do SI, Lee YI (2001b) The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade. J Biol Chem 276: 16969–16977

    Article  PubMed  CAS  Google Scholar 

  • Levrero M, Balsano C, Natoli G, Acantaggiati ML, Elfassi E (1990) Hepatitis B virus X protein transactivates the long terminal repeats of human immunodeficiency virus type 1 and 2. J Virol 64:3082–3086

    PubMed  CAS  Google Scholar 

  • Li J, Tang Z, Liu K (1996) Application of radiolabeled anti-HBx monoclonal antibody for HCC targeting therapy. Zhonghua Yi Xue Za Zhi 76:271–274

    PubMed  CAS  Google Scholar 

  • Li J, Ou JH (2001) Differential regulation of hepatitis B virus gene expression by the Sp1 transcription factor. J Virol 75:8400–8406

    Article  PubMed  CAS  Google Scholar 

  • Lian Z, Pan J, Liu J, Zhang S, Zhu M, Arbuthnot P, Kew M, Feitelson MA (1999) The translation initiation factor, hu-Sui l may be a target of hepatitis B X antigen in hepatocarcinogenesis. Oncogene 18:1677–1687

    Article  PubMed  CAS  Google Scholar 

  • Lin MH, Lo SC (1989) Dimerization of hepatitis B viral X protein synthesized in a cell-free system. Biochem Biophys Res Commun 164:14–21

    Article  PubMed  CAS  Google Scholar 

  • Lin Y, Nomura T, Cheong J, Dorjsuren D, Iida K, Murakami S (1997) Hepatitis B virus X protein is a transcriptional modulator that communicates with transcription factor IIB and the RNA polymerase 11 subunit 5. J Biol Chem 272:7132–7139

    Article  PubMed  CAS  Google Scholar 

  • Livezey KW, Negorev D, Simon D (2002) Increased chromosomal alterations and micronuclei formation in human hepatoma HepG2 cells transfected with the hepatitis B virus HBX gene. Mutat Res 505:63–74

    Article  PubMed  CAS  Google Scholar 

  • Lucito R, Schneider RJ (1992) Hepatitis B virus X protein activates transcription factor NF-kappa Bwithout a requirement for protein kinase C. J Virol 66:983–991

    PubMed  CAS  Google Scholar 

  • Madden CR, Finegold MJ, Slagle BL (2001) Hepatitis B virus X protein acts as a tumor promoter in development of diethylnitrosamine-induced preneoplastic lesions. J Virol 75:3851–3858

    Article  PubMed  CAS  Google Scholar 

  • Maguire HF, Hoeffler JP, Siddiqui A (1991) HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions. Science 252:842–844

    Article  PubMed  CAS  Google Scholar 

  • Majano P, Lara-Pezzi P, Lopez-Cabrera M, Apolinario A, Moreno-Otero R, Garcia-Menzon C (2001) Hepatitis B virus X protein transactivates inducible nitric oxide synthase gene promoter through the proximal nuclear factor kappaB-binding site: Evidence that cytoplasmic location of X protein is essential for gene transactvation. Hepatology 34:1218–1224

    Article  PubMed  CAS  Google Scholar 

  • Mahe Y, Mukaida N, Kuno K, Akiyama M, Ikeda N, Matsushima K, Murakami S (1991) Hepatitis B virus X protein transactivates human interleukin-8 gene through acting nuclear factor kB and CCAAT/enhancer-binding protein-like cis elements. J Biol Chem 266:13759–13763

    PubMed  CAS  Google Scholar 

  • Marriott SJ, Lee TH, Slagle BL, Butel JS (1996) Activation of the HTLV-I long terminal repeat by the hepatitis B virus X protein. Virology 224:206–213

    Article  PubMed  CAS  Google Scholar 

  • McCaffrey AP, Nakai H, Pandey K, Huang Z, Salazar FH, Xu H, Wieland SF, Marion PL, Kay MA (2003) Inhibition of hepatitis B virus in mice by RNA interference. Nat Biotechnol 21:639–644

    Article  PubMed  CAS  Google Scholar 

  • Menzo S, Clementi M, Alfani E, Bagnarelli P, Iacovacci S, Manzin A, Dandri M, Natoli G, Levrero M, Carloni G (1993) Trans-activation of epidermal growth factor receptor gene by the hepatitis B virus X-gene product. Virology 196:878–882

    Article  PubMed  CAS  Google Scholar 

  • Miller RH, Robinson WS (1986) Common evolutionary origin of hepatitis B virus and retroviruses. Proc Natl Acad Sci USA 83:2531–2535

    Article  PubMed  CAS  Google Scholar 

  • Moriarty AM, Alexander H, Lerner RA, Thornton GB (1985) Antibodies to peptides detect new hepatitis B antigen: serological correlation with hepatocellular carcinoma. Science 227:429–433

    Article  PubMed  CAS  Google Scholar 

  • Moriya K, Matsukura M, Kurokawa K, Koike K (1996) In vivo inhibition of hepatitis B virus gene expression by antisense phosphorothioate oligonucleotides. Biochem Biophys Res Commun 218:217–223

    Article  PubMed  CAS  Google Scholar 

  • Murakami S, Cheong JH, Kaneko S (1994) Human hepatitis virus X gene encodes a regulatory domain that represses transactivation of X protein. J Biol Chem 269:15118–15123

    PubMed  CAS  Google Scholar 

  • Murakami S (2001) Hepatitis B virus X protein: a multifunctional viral regulator. J Gastroenterol 36:651–660

    Article  PubMed  CAS  Google Scholar 

  • Nakatake H, Chisaka O, Yamamoto S, Matsubara K, Koshy R (1993) Effect of X protein on transactivation of hepatitis B virus promoters and on viral replication. Virology 195:305–314

    Article  PubMed  CAS  Google Scholar 

  • Natoli G, Avantaggiati ML, Chirillo P, Costanzo A, Artini M, Balsano C, Levrero M (1994). Induction of the DNA-binding activity of c-jun/c-fos heterodimers by the hepatitis B virus transactivator pX. Mol Cell Biol 14:989–998

    PubMed  CAS  Google Scholar 

  • Nijhara R, Jana SS, Goswami SK, Kumar V, Sarkar DP (2001a) An internal segment (residues 58–119) of the hepatitis B virus X protein is sufficient to activate MAP kinase pathways in mouse liver. FEBS Lett. 504:59–64

    Article  PubMed  CAS  Google Scholar 

  • Nijhara R, Jana SS, Goswami SK, Rana A, Majumdar SS, Kumar V, Sarkar DP (2001b) Sustained activation of mitogen-activated protein kinases and activator protein 1 by the hepatitis B virus X protein in mouse hepatocytes in vivo. J Virol 75:10348–10358

    Article  PubMed  CAS  Google Scholar 

  • Oelgeschlager T (2002) Regulation of RNA polymerase II activity by CTD phosphorylation and cell cycle control. J Cell Physiol 190:160–169

    Article  PubMed  CAS  Google Scholar 

  • Oh S, Kim N, Lee Y (1998) Identification of differentially expressed genes in human hepatoblastoma cell line (HepG2) and HBV-X transfected hepatoblastoma cell line (HepG2-4x). Mol Cell 8:212–218

    CAS  Google Scholar 

  • Op De Beeck A, Caillet-Fauquet P (1997) Viruses and the cell cycle. Prog Cell Cycle Res 3:1–19

    Article  Google Scholar 

  • Park US, Park SK, Lee YI, Park JG, Lee YI (2000) Hepatitis B virus-X protein upregulates the expression of p21waf1/cip1 and prolongs G1→S transition via a p53-independent pathway in human hepatoma cells. Oncogene 19:3384–3394

    Article  PubMed  CAS  Google Scholar 

  • Paterlini P, Poussin K, Kew M, Franco D, Brechot C (1995) Selective accumulation of the X transcript of hepatitis B virus in patients negative for hepatitis B surface antigen with hepatocellular carcinoma. Hepatology. 21:313–321

    PubMed  CAS  Google Scholar 

  • Perini G, Oetjen E, Green MR (1999) The hepatitis B pX protein promotes dimerization and DNA binding of cellular basic region/leucine zipper proteins by targeting the conserved basic region. J Biol Chem 274:13970–13977

    Article  PubMed  CAS  Google Scholar 

  • Poussin K, Dienes H, Sirma H, Urban S, Beaugrand M, Franco D, Schirmacher P, Brechot C, Paterlini Brechot P (1999) Expression of mutated hepatitis B virus X genes in human hepatocellular carcinomas. Int J Cancer 80:497–505

    Article  PubMed  CAS  Google Scholar 

  • Qadri I, Maguire HF, Siddiqui A (1995) Hepatitis B virus transactivator protein X interacts with the TATA-binding protein. Proc Natl Acad Sci USA 92:1003–1007

    Article  PubMed  CAS  Google Scholar 

  • Qadri I, Conaway JW, Conaway RC, Schaack J, Siddiqui A (1996) Hepatitis B virus trans activator protein, HBx, associates with the components of TFIIH and stimulates the DNA helicase activity of TFIIH. Proc Natl Acad Sci USA 93:10578–10583

    Article  PubMed  CAS  Google Scholar 

  • Qiao L, Leach K, McKinstry R, Gilfor D, Yacoub A, Park JS, Grant S, Hylemon PB, Fisher PB, Dent P (2001) Hepatitis B virus X protein increases expression of p21(Cip-l/WAF1/MDM) and p27(Kip-1) in primary mouse hepatocytes, leading to reduced cell cycle progression. Hepatology 34:906–917

    Article  PubMed  CAS  Google Scholar 

  • Reddi H, Kumar R, Jain SK, Kumar V (2003) A carboxy-terminal region of the hepatitis B virus X protein promotes DNA interaction of CREB and mimics the native protein for transactivation function. Virus Genes 26:227–238

    Article  PubMed  CAS  Google Scholar 

  • Reddi H, Kumar V (2004) Self-association of the hepatitis B virus X protein in the yeast two-hybrid system. Biochem Biophys Res Commun 317:1017–1022

    Article  PubMed  CAS  Google Scholar 

  • Reifenberg K, Nusser P, Lohler J, Spindler G, Kuhn C, von Weizsacker F, Kock J (2002) Virus replication and virion export in X-deficient hepatitis B virus transgenic mice. J Gen Virol 83:991–996

    PubMed  CAS  Google Scholar 

  • Renner M, Haniel A, Burgelt E, Hofschneider PH, Koch W (1995) Transactivating function and expression of the x gene of hepatitis B virus. J Hepatol 23:53–65

    Article  PubMed  CAS  Google Scholar 

  • Ritter SE, Whitten TM, Quets AT, Schloemer RH (1991) An internal domain of the hepatitis Bvirus X antigen is necessary for transactivating activity. Virology 182:841–845

    Article  PubMed  CAS  Google Scholar 

  • Rossner MT, Jackson RJ, Murray K (1990) Modulation of expression of the hepatitis B virus surface antigen gene by the viral X-gene product. Proc R Soc Lond B Biol Sci 241:51–58

    Article  CAS  Google Scholar 

  • Rossner MT (1992) Hepatitis B virus X-gene product: a promiscuous transcriptional activator. J Med Virol 36:101–117

    Article  PubMed  CAS  Google Scholar 

  • Runkel L, Fischer M, Schaller H (1993) Two-codon insertion mutations of the HBx define two separate regions necessary for its trans-activation function. Virology 197:529-536

    Google Scholar 

  • Schaefer S, Gerlich WH (1995) In vitro transformation by hepatitis B virus DNA. Intervirology 38:143–154

    PubMed  CAS  Google Scholar 

  • Schek N, Bartenschlager R, Kuhn C, Schaller H (1991) Phosphorylation and rapid turnover of hepatitis B virus X-protein expressed in HepG2 cells from a recombinant vaccinia virus. Oncogene 6:1735–1744

    PubMed  CAS  Google Scholar 

  • Schluter V, Meyer M, Hofschneider PH, Koshy R, Caselmann WH (1994) Integrated hepatitis Bvirus X and 3′ truncated preS/S sequences derived from human hepatomas encode functionally active transactivators. Oncogene 9:3335–3344

    PubMed  CAS  Google Scholar 

  • Seeger C, Ganem D, Varmus HE (1984) The cloned genome of ground squirrel hepatitis virus is infectious in the animal. Proc Natl Acad Sci USA 81:5849–5852

    Article  PubMed  CAS  Google Scholar 

  • Seto E, Yen TS, Peterlin BM, Ou JH (1988) Trans-activation of the human immunodeficiency virus long terminal repeat by the hepatitis B virus X protein. Proc Natl Acad Sci USA 85:8286–8290

    Article  PubMed  CAS  Google Scholar 

  • Seto E, Mitchell PJ, Yesn TS (1990) Tranactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature 344:72–74

    Article  PubMed  CAS  Google Scholar 

  • Shapiro P (2002) Ras-MAP kinase signaling pathways and control of cell proliferation: relevance to cancer therapy. Crit Rev Clin Lab Sci 39:285–330

    Article  PubMed  CAS  Google Scholar 

  • Shih WL, Kuo ML, Chuang SE, Cheng AL, Doong SL (2003) Hepatitis B virus X protein activates a survival signaling by linking SRC to phosphatidylinositol 3-kinase. J Biol Chem 278:31807–31813

    Article  PubMed  CAS  Google Scholar 

  • Shin EC, Shin JS, Park JH, Kim H, Kim SJ (1999) Expression of fas ligand in human hepatoma cell lines: role of hepatitis-B virus X (HBX) in induction of Fas ligand. Int J Cancer 82:587–591

    Article  PubMed  CAS  Google Scholar 

  • Shirakata Y, Kawada M, Fujiki Y, Sano H, Oda M, Yaginuma K, Kobayashi M, Koike K (1989) The X gene of hepatitis B virus induced growth stimulation and tumorigenic transformation of mouse NIH3T3 cells. Jpn J Cancer Res 80:617–621

    Article  PubMed  CAS  Google Scholar 

  • Shirakata Y, Koike K (2003) Hepatitis B virus X protein induces cell death by causing loss of mitochondrial membrane potential. J Biol Chem 278:22071–22078

    Article  PubMed  CAS  Google Scholar 

  • Shlomai A, Shaul Y (2003) Inhibition of hepatitis B virus expression and replication by RNA interference. Hepatology 37:764–770

    Article  PubMed  CAS  Google Scholar 

  • Singh M, Kumar V (2003) Transgenic mouse models of hepatitis B virus-associated hepatocellular carcinoma. Rev Med Virol 13:243–253

    Article  PubMed  CAS  Google Scholar 

  • Siddiqui A, Gaynor R, Srinivasan A, Mapoles J, Farr RW (1989) Trans-activation of viral enhancers including long terminal repeat of the human immunodeficiency virus by the hepatitis B virus X protein. Virology 169:479–484

    Article  PubMed  CAS  Google Scholar 

  • Sirma H, Weil R, Rosmorduc O, Urban S, Israel A, Kremsdorf D, Brechot C (1998) Cytosol is the prime compartment of hepatitis B virus X protein where it colocalizes with the proteasome. Oncogene 16:2051–2063

    Article  PubMed  CAS  Google Scholar 

  • Sirma H, Giannini C, Poussin K, Paterlini P, Kremsdorf D, Brechot C (1999) Hepatitis B virus X mutants, present in hepatocellular carcinoma tissue abrogate both the antiproliferative and transactivation effects of HBx. Oncogene 18:4848–4859

    Article  PubMed  CAS  Google Scholar 

  • Slagle BL, Lee TH, Medina D, Finegold MJ, Butel JS (1996) Increased sensitivity to the hepatocarcinogen diethylnitrosamine in transgenic mice carrying the hepatitis B virus X gene. Mol Carcinog 15:261–269

    Article  PubMed  CAS  Google Scholar 

  • Sohn S, Jaitovitch-Groisman I, Benlimame N, Galipeau J, Batist G, Alaoui-Jamali MA (2000) Retroviral expression of the hepatitis B virus x gene promotes liver cell susceptibility to carcinogen-induced site specific mutagenes is. Mutat Res 460:17–28

    Article  PubMed  CAS  Google Scholar 

  • Spandau DF, Lee CH (1988) Trans-activation of viral enhancers by the hepatitis B virus X protein. J Virol 62:427–434

    PubMed  CAS  Google Scholar 

  • Su F, Schneider RJ (1996). Hepatitis B virus HBx protein activates transcription factor NF-kappaB by acting on multiple cytoplasmic inhibitors of rel-related proteins. J. Virol 70:4558–4566

    PubMed  CAS  Google Scholar 

  • Su F, Theodosis CN, Schneider RJ (2001) Role of NF-kappaB and myc proteins in apoptosis induced by hepatitis B virus HBx protein. J Virol 75:215–225

    Article  PubMed  CAS  Google Scholar 

  • Su Q, Schroder CH, Hofmann WJ, Otto G, Pichlmayr R, Bannasch P (1998) Expression of hepatitis B virus X protein in HBV-infected human livers and hepatocellular carcinomas. Hepatology 27:1109–1120

    Article  PubMed  CAS  Google Scholar 

  • Sun BS, Zhu X, Clayton MM, Pan J, Feitelson MA (1998) Identification of a protein isolated from senescent human cells that binds to hepatitis B virus X antigen. Hepatology 27:228–239

    Article  PubMed  CAS  Google Scholar 

  • Suzuki T, Masui N, Kajino K, Saito I, Miyamura T (1989) Detection and mapping of spliced RNA from a human hepatoma cell line transfected with the hepatitis B virus genome. Proc Natl Acad Sci USA 86:8422–8426

    Article  PubMed  CAS  Google Scholar 

  • Takada S, Koike K (1990) Trans-activation function of a 3′ truncated X gene-cell fusion product from integrated hepatitis B virus DNA in chronic hepatitis tissues. Proc Natl Acad Sci USA 87:5628–5632

    Article  PubMed  CAS  Google Scholar 

  • Takada S, Kido H, Fukutomi A, Mori T, Koike K (1994) Interaction of hepatitis B virus X protein with a serine protease, tryptase TL2 as an inhibitor. Oncogene 9:341–348

    PubMed  CAS  Google Scholar 

  • Takada S, Tsuchida N, Kobayashi M, Koike K (1995) Disruption of the function of tumor-suppressor gene p53 by the hepatitis B virus X protein and hepatocarcinogenesis. J Cancer Res Clin Oncol1 21:593–601

    Article  Google Scholar 

  • Tarn C, Lee S, Hu Y, Ashendel C, Andrisani OM (2001) Hepatitis B virus X protein differentially activates RAS-RAF-MAPK and JNK pathways in X-transforming versus nontransforming AML12 hepatocytes. J Biol Chem 276:34671–34680

    Article  PubMed  CAS  Google Scholar 

  • Tarn C, Zou L, Hullinger RL, Andrisani OM (2002) Hepatitis B virus X protein activates the p38 mitogen-activated protein kinase pathway in dedifferentiated hepatocytes. J Virol 76:9763–9772

    Article  PubMed  CAS  Google Scholar 

  • Terradillos O, Billet O, Renard CA, Levy R, Molina T, Briand P, Buendia MA (1997) The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice. Oncogene 14:395–404

    Article  PubMed  CAS  Google Scholar 

  • Terradillos O, Pollicino T, Lecoeur H, Tripodi M, Gougeon ML, Tiollais P, Buendia MA (1998) p53-independent apoptotic effects of the hepatitis B virus HBx protein in vivo and in vitro. Oncogene 17:2115–2123

    Article  PubMed  CAS  Google Scholar 

  • Terradillos O, de La Coste A, Pollicino T, Neuveut C, Sitterlin D, Lecoeur H, Gougeon ML, Kahn A, Buendia MA (2002) The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver. Oncogene 21:377–386

    Article  PubMed  CAS  Google Scholar 

  • Tiollais P, Charnay P, Vyas GN (1981) Biology of hepatitis B virus. Science 213:406–411

    Article  PubMed  CAS  Google Scholar 

  • Truant R, Antunovic J, Greenblatt J, Prives C, Cromlish JA (1995) Direct interaction of the hepatitis B virus HBx protein with p53 leads to inhibition by HBx of p53 response element-directed transactivation. J Virol 69:1851–1859

    PubMed  CAS  Google Scholar 

  • Tsuei DJ, Hsu TY, Chen JY, Chang MH, Hsu HC, Yang CS (1994) Analysis of integrated hepatitis B virus DNA and flanking cellular sequences in a childhood hepatocellular carcinoma. J Med Virol 42:287–293

    Article  PubMed  CAS  Google Scholar 

  • Tu H, Bonura C, Giannini C, Mouly H, Soussan P, Kew M, Paterlini-Brechot P, Brechot C, Kremsdorf D (2001) Biological impact of natural COOH-terminal deletions of hepatitis B virus X protein in hepatocellular carcinoma tissues. Cancer Res 61:7803–7810

    PubMed  CAS  Google Scholar 

  • Tuttleman JS, Pugh JC, Summers JW (1986) In vitro experimental infection of primary duck hepatocyte cultures with duck hepatitis B virus. J Virol 58:17–25

    PubMed  CAS  Google Scholar 

  • Twu JS, Schloemer RH (1987) Transcriptional trans-activating function of hepatitis B virus. J Virol 61:3448–3453

    PubMed  CAS  Google Scholar 

  • Twu JS, Robinson WS (1989) Hepatitis B virus X gene can transactivate heterologous viral sequences. Proc Natl Acad Sci USA 86:2046–2050

    Article  PubMed  CAS  Google Scholar 

  • Twu JS, Lai MY, Chen DS, Robinson WS (1993) Activation of protooncogene c-jun by the X protein of hepatitis B virus. Virology 192:346–350

    Article  PubMed  CAS  Google Scholar 

  • Ueda H, Ullrich SJ, Gangemi JD, Kappel CA, Ngo L, Feitelson MA, Jay G (1995) Functional inactivation but not structural mutation of p53 causes liver cancer. Nat Genet 9:41–47

    Article  PubMed  CAS  Google Scholar 

  • Urban S, Hildt E, Eckerskorn C, Sirma H, Kekule A, Hofschneider PH (1997) Isolation and molecular characterization of hepatitis B virus X-protein from a baculovirus expression system. Hepatology 26:1045–1053

    Article  PubMed  CAS  Google Scholar 

  • Wang HD, Yuh CH, Dang CV, Johnson DL (1995) The hepatitis B virus X protein increases the cellular level of TATA-binding protein, which mediates transactivation of RNA polymerase genes. Mol Cell Biol 15:6720–6728

    PubMed  CAS  Google Scholar 

  • Wang HD, Trivedi A, Johnson DL (1997) Hepatitis B virus X protein induces RNA polymerase III-dependent gene transcription and increases cellular TATA-binding protein by activating the Ras signaling pathway. Mol Cell Biol 17:6838–6846

    PubMed  CAS  Google Scholar 

  • Wang HD, Trivedi A, Johnson DL (1998) Regulation of RNA polymerase I-dependent pro moters by the hepatitis B virus X protein via activated Ras and TATA-binding protein. Mol Cell Biol 18:7086–7094

    PubMed  CAS  Google Scholar 

  • Wang W, Carey M, Gralla JD (1992) Polymerase II promoter activation: closed complex formation and ATP-driven start site opening. Science 255:450–453

    Article  PubMed  CAS  Google Scholar 

  • Wang XW, Gibson MK, Vermeulen W, Yeh H, Forrester K, Sturzbecher HW, Hoeijmakers JH, Harris CC (1995) Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Cancer Res 55:6012–6016

    PubMed  CAS  Google Scholar 

  • Wei w, Dorjsuren D, Lin Y, Qin W, Nomura T, Hayashi N, Murakami S (2001) Direct interaction between the subunit RAP30 of transcription factor IIF (TFIIF) and RNA polymerase subunit 5, which contributes to the association between TFIIF and RNA polymerase II. J Biol Chem 276:12266–12273

    Article  PubMed  CAS  Google Scholar 

  • Weil R, Sirma H, Giannini C, Kremsdorf D, Bessia C, Dargemont C, Brechot C, Israel A (1999) Direct association and nuclear import of the hepatitis B virus X protein with the NF-kappaB inhibitor IkappaBalpha. Mol Cell Biol 19:6345–6354

    PubMed  CAS  Google Scholar 

  • Weinberg M, Passman M, Kew M, Arbuthnot P (2000) Hammerhead ribozyme-rnediated inhibition of hepatitis B virus X gene expression in cultured cells. J Hepatol 33:142–151

    Article  PubMed  CAS  Google Scholar 

  • Williams JS, Andrisani OM (1995) The hepatitis B virus X protein targets the basic region-leucine zipper domain of CREB. Proc Natl Acad Sci USA 92:3819–3823

    Article  PubMed  CAS  Google Scholar 

  • Wollersheim M, Debelka U, Hofschneider PH (1988) A transactivating function encoded in the hepatitis B virus X gene is conserved in the integrated state. Oncogene 3:545–552

    PubMed  CAS  Google Scholar 

  • Wu CG, Salvay DM, Forgues M, Valerie K, Farnsworth J, Markin RS, Wang XW (2001) Distinctive gene expression profiles associated with Hepatitis B virus x protein. Oncogene 20:3674–3682

    Article  PubMed  CAS  Google Scholar 

  • Wu CG, Forgues M, Siddique S, Farnsworth J, Valerie K, Wang XW (2002) SAGE transcript profiles of normal primary human hepatocytes expressing oncogenic hepatitis B virus X protein. FASEB J 16:1665–1667

    Article  PubMed  CAS  Google Scholar 

  • Xu Z, Yen TS, Wu L, Madden CR, Tan W, Slagle BL, Ou JH (2002) Enhancement of hepatitis B virus replication by its X protein in transgenic mice. J Virol 76:2579–2584

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto S, Mita E, Nakatake H, Takimoto M, Koshy R, Matsubara K (1993) Transactivating function of integrated hepatitis B virus. Biochem Biophys Res Commun 197:1209–1215

    Article  PubMed  CAS  Google Scholar 

  • Yoo YD, Veda H, Park K, Flanders KC, Lee YI, Jay G, Kim SJ (1996) Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator. Role in HBV pathogenesis. J Clin Invest 97:388–395

    Article  PubMed  CAS  Google Scholar 

  • Zahm P, Hofschneider PH, Koshy R (1988) The HBV X-ORF encodes a transactivator: a potential factor in viral hepatocarcinogenesis. Oncogene 3:169–177

    PubMed  CAS  Google Scholar 

  • Zhang Z, Torii N, Furusaka A, Malayaman N, Hu Z, Liang TJ (2000) Structural and functional characterization of interaction between hepatitis B virus X protein and the proteasome complex. J Biol Chem 2000 275:15157–15165

    CAS  Google Scholar 

  • Zheng Y, Li J, Johnson DL, Ou JH (2003) Regulation of hepatitis B virus replication by the Ras-mitogen-activated protein kinase signaling pathway. J Virol 77:7707–7712

    Article  PubMed  CAS  Google Scholar 

  • Zhou DX, Taraboulos A, Ou JH, Yen TS (1990) Activation of class I major histocompatibility complex gene expression by hepatitis B virus. J Virol 64:4025–4028

    PubMed  CAS  Google Scholar 

  • Zhou MX, Watabe M, Watabe K (1994) The X-gene of human hepatitis B virus transactivates the c-jun and alpha-fetoprotein genes. Arch Virol 134:369–378

    Article  PubMed  CAS  Google Scholar 

  • Zhou YZ, Butel JS, Li PJ, Finegold MJ, Melnick JL (1987) Integrated state of subgenomic fragments of hepatitis B virus DNA in hepatocellular carcinoma from mainland China. J Natl Cancer Inst 79:223–231

    PubMed  CAS  Google Scholar 

  • Zoulim F, Saputelli J, Seeger C (1994) Woodchuck hepatitis virus X protein is required for viral infection in vivo. J Virol 68:2026–2030

    PubMed  CAS  Google Scholar 

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  1. Virology Group, International Centre for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, P.O. Box 10504, New Delhi, 110067, India

    V. Kumar

  2. Department of Biochemistry, University of Delhi South Campus, Benito Juarez Marg, New Delhi, 110021, India

    D. P. Sarkar

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Kumar, V., Sarkar, D.P. (2004). Hepatitis B Virus X Protein: Structure-Function Relationships and Role in Viral Pathogenesis. In: Gossen, M., Kaufmann, J., Triezenberg, S.J. (eds) Transcription Factors. Handbook of Experimental Pharmacology, vol 166. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-18932-6_12

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