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The X-gene of human hepatitis B virus transactivates the c-jun and α-fetoprotein genes

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Summary

The X-gene product of human hepatitis B virus is a transacting transcriptional factor which activates a variety of heterologous viral and host promoters/enhancers. We have found that the X-gene product can significantly transactivate the regulatory sequences located at the 5′-upstream of the c-jun oncogene when a reporter plasmid containing the sequences was co-transfected to HepG2 cells with an X-gene expression plasmid. The results of mutational analysis indicate that the X-gene activation requires the AP-1 sequence of the c-jun gene. Furthermore, we also found that the X-gene is capable of activating the 5′-upstream sequence of the α-fetoprotein gene. There are at least two elements that respond to the X-gene transactivation. One is located in the sequences between −5100 and −2900, and the other is at the C/EBP site. Therefore, the X-gene activates the c-jun and α-fetoprotein genes through different host factors, namely AP-1 and C/EBP, respectively. The results of c-jun activation by the X-gene strongly support the previous hypothesis that the X-gene may play a critical role in the development of hepatocellular carcinoma.

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References

  1. Angel P, Hattori K, Smeal T, Karin M (1988) The jun protooncogen is positively autoregulated by its product, Jun/AP-1. Cell 55: 875–885

    Google Scholar 

  2. Beasley RP, Hwang LY (1984) In: Vyan GN, Dienstag JL, Hootnagle JH (eds) Viral hepatitis and liver disease. Crune and Stratton, New York, pp 209–224

    Google Scholar 

  3. Chisari FV, Filippi P, McLachlan A, Milich DR, Riggs M (1986) Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice. J Virol 60: 880–887

    Google Scholar 

  4. Dejean A, Bougueleret L, Grzeschik KH, Tiollais P (1986) Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in hepatocellular carcinoma. Nature 322: 70–72

    Google Scholar 

  5. Fisch TM, Prywes R, Roeder R (1987) c-fos sequence necessary for basal expression and induction by epidermal growth factor, 12-0-tetradecanoyl phorbol-13-acetate and the calcium ionophore. Mol Cell Biol 7: 3490–3502

    Google Scholar 

  6. Gorman CM, Moffat L, Howard BH (1982) Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol 2: 1044–1051

    Google Scholar 

  7. Groot R, Foulkes N, Mulder M, Kruijer W, Sassocorsi P (1991) Positive regulation of jun/AP-1 by ElA. Mol Cell Biol 11: 192–201

    Google Scholar 

  8. Ganem D, Varmus HE (1987) The moleculer biology of the hepatitis B viruses. Annu Rev Biochem 56: 651–693

    Google Scholar 

  9. Haritani H, Esumi M, Uchida T, Shikata T (1991) Oncogene expression in the liver tissue of patients with nonneoplastic liver disease. Cancer 67: 2594–2598

    Google Scholar 

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

    Google Scholar 

  11. Hollinger FB, Robinson WS, Purcell RH, Gerin JL, Ticehurst J (1990) Viral hepatitis. Raven Press, New York, pp 73–138

    Google Scholar 

  12. Hsu TY, Moroy T, Etiemble J, Louise A, Trepo C, Tiollais P, Buendia MA (1988) Activation of c-myc by woodchuck hepatitis virus insertion in hepatocellular carcinoma. Cell 55: 627–635

    Google Scholar 

  13. Hu KQ, Vierling JM, Siddiqui A (1990) Transactivation of HLA-DR gene by hepatitis B virus X-gene product. Proc Natl Acad Sci USA 87: 7140–7144

    Google Scholar 

  14. 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

    Google Scholar 

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

    Google Scholar 

  16. Miyaki M, Sato C, Gotanda T, Matsui T, Mishiro S, Imai M, Mayumi M (1986) Integration of region X of hepatitis B virus genome in human primary hepatocellular carcinomas propagated in nude mice. J Gen Virol 67: 1449–1454

    Google Scholar 

  17. Morello D, Fitzgerald MH, Babinet C, Fausto N (1990) c-myc, c-fos, and c-jun regulation in the regenerating livers of normal and H2K/c-myc transgenic mice. Mol Cell Biol 10: 3185–3193

    Google Scholar 

  18. Moriarty AM, Hoyer BB, Shih JWK, Gerin JL, Hamer DH (1981) Expression of the hepatitis B virus surface antigen gene in cell culture by lusing a simia virus 40 vector. Proc Natl Acad Sci USA 78: 2606–2610

    Google Scholar 

  19. Nagata K, Ohtani K, Nakamura M, Sugamura K (1989) Activation of endogenous c-fos proto-oncogene expression by human T-cell leukemia virus type I-encoded p40rax protein in the human T-cell line, Jurkat. J Virol 63: 3220–3226

    Google Scholar 

  20. Nagaya T, Nakamura T, Tokino T, Tsurimoto T, Imai M, Mayumi T, Kamino K, Yamamura K, Matsubara K (1987) The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma. Genes Dev 1: 773–782

    Google Scholar 

  21. Popper H, Roth L, Purcell RH, Tennant BC, Gerin JL (1987) Hepatocarcinogenicity of the woodchuck hepatitis virus. Proc Natl Acad Sci USA 84: 866–870

    Google Scholar 

  22. Ransone L, Verma M (1990) Nuclear proto-oncogenes fos and jun. Annu Rev Cell Biol 6: 539–557

    Google Scholar 

  23. Sakai M, Mirinaga T, Urano Y, Watanabe K, Wegmann TG, Tamaoki T (1985) The human alpha-fetoprotein gene. Sequence organization and the 5′ flanking region. J Biol Chem 260: 5055–5060

    Google Scholar 

  24. Schutte J, Minna JD, Birrer MJ (1989) Deregulated expression of human c-jun transforms primary rat embryo cells in cooperation with an activated c-Ha-ras gene and transforms rat-la cells as a single gene. Proc Natl Acad Sci USA 86: 2257–2261

    Google Scholar 

  25. Seto LE, Mitchell PJ, Yen T (1990) Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature 344: 72–74

    Google Scholar 

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

    Google Scholar 

  27. Sherker AH, Marion PL (1991) Hepadenaviruses and hepatocellular carcinoma. Annu Rev Microbiol 45: 475–508

    Google Scholar 

  28. 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

    Google Scholar 

  29. Siddiqui A, Gaynor R, Srinivasan A, Maples 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

    Google Scholar 

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

    Google Scholar 

  31. Szmuness W, Stevens CE, Keram H, Much M, Harley EJ, Hollinger B (1978) Prevalence of hepatitis B virus infection and hepatocellular carcinoma in Chinese-Americans. J Infect Dis 137: 822–829

    Google Scholar 

  32. Twu J, Chu K, Robinson W (1989) Hepatitis B virus X-gene activates kappa B-like enhancer sequences in the long terminal repeat of human immunodeficiency virus 1. Proc Natl Acad Sci USA 86: 5168–5172

    Google Scholar 

  33. Twu J, Rosen CA, Haseltine WA, Robinson WS (1989) Identification of a region within the human immunodeficiency virus type 1 long terminal repeat that is essential for transactivation by the hepatitis B virus gene X. J Virol 63: 2857–2860

    Google Scholar 

  34. Twu JS, Shloemer RH (1987) Transcriptional transactivating function of hepatitis B virus. J Virol 61: 3448–3453

    Google Scholar 

  35. Vandeyar M, Weiner M, Hutton C, Batt C (1988) A simple and rapid method for the selection of oligodeoxynucleotide-directed mutants. Gene 65: 129

    Google Scholar 

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

    Google Scholar 

  37. Zhang XK, Dong JM, Chiu JF (1990) Regulation of alpha-fetoprotein gene expression by antagonism between AP-1 and the glucocorticoid receptor at their overlapping binding site. J Biol Chem 266: 8248–8254

    Google Scholar 

  38. Zhang XK, Huang DP, Chiu DK, Chiu JF (1987) The expression of oncogenes in human developing liver and hepatomas. Biochem Biophys Res Commun 142: 932–938

    Google Scholar 

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  1. Department of Medical Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, USA

    M. X. Zhou, M. Watabe & K. Watabe

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  1. M. X. Zhou
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  2. M. Watabe
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  3. K. Watabe
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Zhou, M.X., Watabe, M. & Watabe, K. The X-gene of human hepatitis B virus transactivates the c-jun and α-fetoprotein genes. Archives of Virology 134, 369–378 (1994). https://doi.org/10.1007/BF01310574

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  • DOI: https://doi.org/10.1007/BF01310574

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