Advertisement

The PreS2 Activators of the Hepatitis B Virus: Activators of Tumour Promoter Pathways

  • E. Hildt
  • P. H. Hofschneider
Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 154)

Abstract

In addition to causing acute and chronic hepatitis, hepatitis B virus (HBV) is considered to be a major cliological factor in the development of human hepatocellular carcinoma (HCC). Epidemiological studies have demonstrated an approximately 10-fold increase in the relative risk of HCC among HBV carried compared to noncarriers. Almost all HBV-associated HCCs studied so far harbor chromosomally integrated HBV DNA. Integrated viral DNA can encode two types of transcriptional activators, the HBx protein and the PreS2 activators [the large surface proteins (LHBs) and truncated middle surface proteins (MHBs)]. The activator function of the PreS2 activators is based on the cytoplasmic orientation of the PreS2 domain. The PreS2 domain is PKC-dependent phosphorylated. Moreover, the PreS2 domain binds of PKCa/β and triggers a PKC-dependent activation of the c-Raf-1/MAP2-kinase signal transduction cascade, resulting in an activation of transcription factors such as AP-1 and NF-kB. Furthermore, by activation of this signaling cascade, the PreS2 activators cause an increased proliferation rate of hepatocytes. According to the two-step model of carcinogenesis (initiation/promotion), the PreS2 activators could exert a tumour-promoter-like function by activation of the PKC/c-Raf-1/MAP2-kinase signaling cascade: cells harboring critical mutations (initiation) may be positively selected (promotion). Such a multistep process may account for the long latency period in HCC development, but it also leads to the hypothesis that each tumor reflects an individual case.

Keywords

Increase Proliferation Rate Transcriptional Activator Function PreS2 Activator PreS2 Domain Virus Transgenic Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Beasley RP (1988) Hepatitis B virus: the major etiology of hepatocellular carcinoma. Cancer 61: 1942 - 1956PubMedCrossRefGoogle Scholar
  2. Beasley RP, Hwang LY, Lin CC, Chien CS (1981) Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 2: 1129 - 1133PubMedCrossRefGoogle Scholar
  3. Benn J, Schneider RJ (1994) Hepatitis B virus pX protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. Proc Natl Acad Sci USA 91: 10350-10354Google Scholar
  4. Benn J, Schneider RJ (1995) Hepatitis B virus HBx protein deregulates cell cycle checkpoint controls. Proc Natl Acad Sci USA 92: 11215 - 11219PubMedCrossRefGoogle Scholar
  5. Bruss V, Lu R, Thomssen R, Gerlich W (1994) Post translational alterations in the trans-membrane topology of the hepatitis B virus large envelope protein. EMBO J 13: 22732279Google Scholar
  6. Buendia MA (1992) Mammalian hepatitis B viruses and primary liver cancer. Semin Cancer Biol 3: 309 - 320PubMedGoogle Scholar
  7. Caselmann WH (1996) Trans-activation of cellular genes by hepatitis B virus proteins: a possible mechanism of hepatocarcinogenesis. Adv Virus Res 47: 253 - 302PubMedCrossRefGoogle Scholar
  8. Caselmann WH, Meyer M, Kekulé AS, Lauer U, Hofschneider PH, Koshy R (1990) A trans-activator function is generated by integration of hepatitis B virus preS/S sequences in human hepatocellular carcinoma DNA. Proc Natl Acad Sci USA 87: 2970 - 2974PubMedCrossRefGoogle Scholar
  9. Chang MH, Chen C, Lai M, Hsu H, Wu T, Kong M, Liang D, Shau W, Chen D (1997) Universal HBNV vaccination in Taiwan and the incidence of HCC in children. N Engl J Med 336 (26): 1855 - 1859PubMedCrossRefGoogle Scholar
  10. Chisari FV (1995) Hepatitis B virus transgenic mice: insights into the virus and the disease. Hepatology 22: 1316 - 1325PubMedGoogle Scholar
  11. Chisari FV (1996) Hepatitis B virus transgenic mice: Models of viral immunobiology and pathogenesis. Curr Top Microbiol 186: 149 - 173CrossRefGoogle Scholar
  12. Chisari FV, Pinkert CA, Milich DR, Filippi P, McLachlan A, Palmiter RD, Brinster RL (1985) A transgenic mouse model of the chronic hepatitis B virus surface antigen carrier state. Science 230: 1157 - 1160PubMedCrossRefGoogle Scholar
  13. Chisari FV, Filippi P, McLachlan A, Milich D, Riggs M, Lee S, Palmiter RD, Brinster RL (1986) Expression of hepatitis B virus large envelope protein inhibits hepatitis B surface antigen secretion in transgenic mice. J Virol 60: 6909 - 6913Google Scholar
  14. Chisari FV, Klopching K, Moryiama T, Pasquinelli C, Dunsford HA, Sell S, Pinkert CA, Brinster RL, Palmiter RD (1989) Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell 59: 1145 - 1156PubMedCrossRefGoogle Scholar
  15. Fazioli F, Minichiello L, Matoskova B, Wong WT, Difiore PP (1993) Eps15 a novel tyrosine kinase substrate exhibits transforming activity. Mol Cell Biol 13: 5814 - 5828PubMedGoogle Scholar
  16. Ganem D (1991) Assembly of hepadnaviral virions and subviral particles. Curr Top Microbiol Immunol 168: 61 - 83PubMedCrossRefGoogle Scholar
  17. Hildt E, Urban S, Lauer U, Hofschneider PH, Kekulé AS (1993) ER-localization and functional expression of the HBV transactivator MHBs`. Oncogene 8: 3359 - 3367PubMedGoogle Scholar
  18. Hildt E, Urban S, Hofschneider PH (1995) Characterization of essential domains for the functionality of the MHBs` transcriptional activator and identification of a minimal MHBs` activator. Oncogene 11: 2055 - 2066PubMedGoogle Scholar
  19. Hildt E, Urban S, Eckerskorn C, Hofschneider PH (1996 a) Isolation of highly purified, functional carboxy-terminally truncated hepitatis B virus middle surface protein activators from eucaryotic expression systems. Hepatology 24: 502 - 507Google Scholar
  20. Hildt E, Saher G, Bruss V, Hofschneider PH (1996b) The hepatitis B virus large surface protein ( LHBs) is a transcriptional transactivator. Virology 225: 235-239Google Scholar
  21. Hildt E, Hofschneider PH, Urban S (1996c) The role of hepatitis B virus in the development of hepatocellular carcinoma. Semin Virol 7: 333 - 347CrossRefGoogle Scholar
  22. Hildt E, Saher G, Munz B, Hofschneider PH (1998) The hepatitis B virus transcriptional activator MHBs` binds to PKC and induces PKC-dependent transcriptional activation of the Raf/MAP-kinase signal transduction pathway (submitted)Google Scholar
  23. Hildt E, Reifenberg K, Hoschneider PH (1998) Activation of cRaf-1/MAP2-kinase signal transduction pathway in transgenic mice producing the preS2 activatis LHBs or MHBst (manuscript in preparation)Google Scholar
  24. Hurtley S, Helenius A (1989) Protein oligomerization in the endoplasmic reticulum. Annu Rev Cell Biol: 5: 277 - 307PubMedCrossRefGoogle Scholar
  25. Jakubczak JL, Chisari FV, Merlino G (1997) Synergy between TGFa and hepatitis B virus surface antigen in hepatocellular proliferation and carcinogenesis. Cancer Res 57 (16): 3606 - 3611PubMedGoogle Scholar
  26. Kekulé AS (1994) Hepatitis B virus transactivator proteins: the trans hypothesis of liver carcinogenesis. In: Bréchot C (ed) Human primary liver cancer: etiological and progression factors. CRG Press, Boca Raton, pp 191 - 210Google Scholar
  27. Kekulé AS, Lauer U, Meyer M, Caselmann WH, Hofschneider PH, Koshy R (1990) The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator. Nature 343: 457 - 461PubMedCrossRefGoogle Scholar
  28. 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 - 745PubMedCrossRefGoogle Scholar
  29. Lauer U, Weiss L, Hofschneider PH, Kekulé AS (1992) The hepatitis B virus preS2/St trans-activator is generated by 3 truncations within a defined region of the S gene. J Virol 66: 5284 - 5289PubMedGoogle Scholar
  30. Lauer U, Weiss L, Lipp M, Hofschneider PH, Kekulé AS (1994) The hepatitis B virus preS2/ St transactivator utilizes AP-1 and other transcription factors for transactivation. Hepatology 19: 23 - 31PubMedGoogle Scholar
  31. Meyer M, Caselmann WH, Schlüter V, Schreck R, Hofschneider PH, Baeuerle PA (1992 a) Hepatitis B virus transactivator MHBst: activation of NF-y13, selective inhibition by antioxidants and integral membrane localization. EMBO J 11: 2991 - 3001Google Scholar
  32. Meyer M, Wiedorn KH, Hofschneider PH, Koshy R, Caselmann WH (1992b) A chromosome 17:7 translocation is associated with a hepatitis B virus DNA integration in human hepatocellular carcinoma DNA. Hepatology 15: 665 - 671PubMedCrossRefGoogle Scholar
  33. Natoli G, Avantaggiati M, Balsano C, de Marzio E, Collepadro D, Elfassi E, Levrero M (1992) Characterization of the hepatitis B virus preS/S region encoded transcriptional transactivator. Virology 187: 663 - 670Google Scholar
  34. Natoli G, Avantaggiati ML, Chirillo P, Puri PL, Lanni A, Balsano C, Levrero M (1994) Ras-and Raf dependent activation of c-jun transcriptional activity by hepatitis B virus trans-activator pX. Oncogene 9: 2837 - 2843PubMedGoogle Scholar
  35. Ostapchuk P, Hearing P, Ganem D (1994) A dramatic shift in the transmembrane topology of a viral envelope glycoprotein accompanies hepatitis B viral morphogenesis. EMBO J 13: 1048 - 1057PubMedGoogle Scholar
  36. Pahl HL, Bäuerle PA (1994) Oxygen and the control of gene-expression. Bioessays 19: 497 - 502CrossRefGoogle Scholar
  37. Parkin DM, Stjernswaerd J, Muir CS (1984) Estimates of the worldwide frequency of twelve major cancers. Bull World Health Org 62: 163 - 182PubMedGoogle Scholar
  38. Rogler CE, Chisari FV (1992) Cellular and molecular mechanisms of hepatocarcinogenesis. Semin Liver Dis 12: 265 - 278PubMedCrossRefGoogle Scholar
  39. Rothmann K, Schnoelzer M, Radziwill G, Hildt E, Moelling K, Schaller H (1998) Host cell-virus cross talk: phosphorylation of a hepatitis B virus envelope protein mediates intracellular signaling. EMBO J (submitted)Google Scholar
  40. Saher G, Hofschneider PH, Hildt E (1998) Increased proliferation of cells stably producing the hepatitis B virus activator MHBst76. Hepatology (submitted)Google Scholar
  41. Schlüter V, Meyer M, Hofschneider PH, Koshy R, Caselmann WH (1994) Integrated hepatitis B virus X and 3 truncated preS/S sequences derived from human hepatomas encode functionally active transactivators. Oncogene 9: 3335 - 3344PubMedGoogle Scholar
  42. Stevenson MA, Pllock S, Coleman S, Calderwood K (1994) X-irradiation, phorbo esters and H2O2 stimulate mitogen activated protein kinase activity in MIH3T3 cells through the formation of reactive oxygen intermediates. Cancer Res 54: 12 - 15PubMedGoogle Scholar
  43. Stibbe W, Gerlich WH (1983) Structural relationship between minor and major proteins of hepatitis B surface antigen. J Virol 46: 626 - 628PubMedGoogle Scholar
  44. Szmuness W (1978) Hepatocellular carcinoma and the hepatitis B virus: evidence for a causal association. Progr Med Vir 24: 40 - 69Google Scholar
  45. Twu JS, Schloemer RH (1987) Transcriptional trans-activating function of hepatitis B virus. J Virol 61: 3448 - 3453PubMedGoogle Scholar
  46. Urban S, Hildt E, Eckerskorn C, Kekulé AS, Hofschneider PH (1996) One-step purification of hepatitis B virus X protein from a baculovirus expression system and its characterization by mass spectrometry. Heptatology 26: 1045 - 1053CrossRefGoogle Scholar
  47. Weiss L, Hildt E, Hofschneider PH (1996) Anti HBV activity of N-acetyl-L-cysteine (NAC): new aspects of a well established drug. J Antivir Res 32: 43 - 53CrossRefGoogle Scholar
  48. Wollersheim M, Delbelka U, Hofschneider PH (1988) A transactivating function encoded in the hepatitis B virus X gene is conserved in the integrated state. Oncogene 3: 545 - 552PubMedGoogle Scholar
  49. Yamamoto S, Nakatake H, Kawamoto M, Koshy R, Matsubara K (1993) Transactivation of cellular promotors by an integrated hepatitis B virus DNA. Biochem Biophys Res Commun 192: 111 - 118PubMedCrossRefGoogle Scholar
  50. Zahm P, Hofschneider PH, Koshy R (1988) The HBV X-ORF encodes a transactivator: a potential factor in viral hepatocarcinogenesis. Oncogene 3: 169 - 177PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin · Heidelberg 1998

Authors and Affiliations

  • E. Hildt
    • 1
  • P. H. Hofschneider
    • 2
  1. 1.Institute of Experimental SurgeryTechnical University of MunichMunichGermany
  2. 2.Max Planck Institute of BiochemistryDepartment of Viral ResearchMartinsriedGermany

Personalised recommendations