1887

Abstract

C-terminally truncated surface proteins of hepatitis B virus (HBV) are frequently translated from genomically integrated viral sequences. They may be relevant for hepatocarcinogenesis by stimulating gene expression. First, we examined the transactivating potential of middle hepatitis B surface protein truncated at amino acid (aa) position 167 (MHBs) on the HBV regulatory element. In transient cotransfection assays using Chang liver or HepG2 cell lines and chloramphenicol acetyl- transferase (CAT) reporter constructs only the HBV enhancer I, but no other HBV regulatory elements like the X promoter, the S1 or S2 promoter or the enhancer II/core promoter could be stimulated by MHBs. Since there is no evidence for a direct interaction of MHBs with DNA, we subsequently analysed whether cellular transcription factors were involved in mediating transactivation. This was tested both with isolated transcription-factor-binding sites and in the natural context of viral and cellular promoter elements. Deletion analysis and electrophoretic mobility shift assays revealed that Sp1,AP1 and NF-kB can mediate transactivation by MHBs. No involvement of CREB, NF1 or the liver- specific factor C/EBP was found. These data indicate that MHBs is a pleiotropic, non-liver-specific transactivator which exerts its effect via ubiquitous cellular transcription factors that are also involved in the regulation of expression of cellular genes relevant for proliferation and inflammation.

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1997-06-01
2024-05-14
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References

  1. Angel P., Imagawa M., Chiu R., Stein B., Imbra R. J., Rahmsdorf H. J., Jonat C., Herrlich P., Karin M. 1987; Phorbol ester-inducible genes contain a common cis-element recognized by a TPA-modulated transacting factor. Cell 49:729–739
    [Google Scholar]
  2. Bauskin A. R., Alkalay I., Ben-Neriah Y. 1991; Redox regulation of a protein tyrosine kinase in the endoplasmic reticulum. Cell 66:685–696
    [Google Scholar]
  3. Caselmann W. H. 1996; Transactivation of cellular genes by hepatitis B virus proteins: a possible mechanism ofhepatocarcinogenesis. Advances in Virus Research 47:253–302
    [Google Scholar]
  4. Caselmann W. H., Meyer M., Kekulé A. S., Lauer U., Hofschneider P. H., Koshy R. 1990; A trans-activator function is generated by integration of hepatitis B virus preS/S sequences in human hepatocellular carcinoma DNA. Proceedings of the National Academy of Sciences USA: 872970–2974
    [Google Scholar]
  5. Devary Y., Gottlieb R. A., Lau L. F., Karin M. 1991; Rapid and preferential activation of the c-jun gene during the mammalian UV response. Molecular and Cellular Biology 11:2804–2811
    [Google Scholar]
  6. Dignam J. D., Lebovitz R. M., Roeder R. G. 1983; Accurate transcription initiation by RNA polymerase II in a soluble extract from mammalian nuclei. Nucleic Acids Research 11:1475–1489
    [Google Scholar]
  7. Faktor O., Shaul Y. 1990; The identification of the hepatitis B virus X gene responsive elements reveals functional similarity of x and HTLV I tax. Oncogene 5:867–872
    [Google Scholar]
  8. Frebourg T., Brison O. 1988; Plasmid vectors with multiple cloning sites and CAT reporter gene for promotor cloning and analysis in animal cells. Gene 65:315–318
    [Google Scholar]
  9. Gonzalez G. A., Montminy M. R. 1989; Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell 59:675–680
    [Google Scholar]
  10. Gustin K., Shapiro M., Lee W., Burk R. D. 1993; Characterization of the role of individual protein binding motifs within the hepatitis B virus enhancer I on X promoter activity using linker scanning mutagenesis. Virology 193:653–660
    [Google Scholar]
  11. Hildt E., Urban S., Lauer U., Hofschneider P. H., Kekulé A. S. 1993; . ER-localization and functional expression of HBV transactivator MHBsfi Oncogene 8:3359–3367
    [Google Scholar]
  12. Hildt E., Urban S., Hofschneider P. H. 1995; Characterization of essential domains for the functionality of the MHBst transcriptional activator and identification of a minimal MHBst activator. Oncogene 11:2055–2066
    [Google Scholar]
  13. Ishii S., Kadonaga J. T., Tjian R., Brady J. N., Merlino G. T., Pastan I. . 1986; Binding of the Sp1 transcription factor by the human Harvey- ras-1 proto-oncogene promoter. Science 232:1410–1413
    [Google Scholar]
  14. Jackson S. P., Tjian R. 1988; O-Glycosylation of eukaryotic transcription factors: implications for mechanisms of transcriptional regulation. Cell 55:125–133
    [Google Scholar]
  15. Jones K. A., Tjian R. 1985; Sp1 binds to promoter sequences and activates herpes simplex virus immediate-early gene transcription in vitro . Nature 317:179–182
    [Google Scholar]
  16. Kadonaga J. T., Jones K. A., Tjian R. 1986; Promoter-specific activation of RNA polymerase II transcription by Sp1. Trends in Biochemical Sciences 11:20–23
    [Google Scholar]
  17. Karin M. 1991; Signal transduction and gene control. Current Opinion in Cell Biology 3:467–473
    [Google Scholar]
  18. Karin M., Smeal T. 1992; Control of transcription factors by signal transduction pathways: the beginning of the end. Trends in Biochemical Sciences 17:418–422
    [Google Scholar]
  19. Kekulé A. S., Lauer U., Meyer M., Caselmann W. H., Hofschneider P. H., Koshy R. 1990; The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator. Nature 334:457–461
    [Google Scholar]
  20. Keyse S. M., Emslie E. A. 1992; Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature 359:644–647
    [Google Scholar]
  21. Lauer U., Weiß L., Hofschneider P. H., Kekulé A. S. 1992; The hepatitis B virus transactivator is generated by 3ʹ-truncation within a defined region of the S gene. Journal of Virology 66:5284–5289
    [Google Scholar]
  22. Lauer U., Weiß L., Lipp M., Hofschneider P. H., Kekulé A. S. 1994; The hepatitis B virus preS2/St transactivator utilizes AP1 and other transcription factors for transactivation. Hepatology 19:23–31
    [Google Scholar]
  23. Lopez-Cabrera M., Letovsky J., Hu K. Q., Siddiqui A. 1991; Transcriptional factor C}EBP binds to and transactivates the enhancer element II of the hepatitis B virus. Virology 183:825–829
    [Google Scholar]
  24. Lowndes N. F., Paul J., Wu J., Allan M. 1989; c-Ha-ras gene bidirectional promoter expressed in vitro : location and regulation. Molecular and Cellular Biology 9:3758–3770
    [Google Scholar]
  25. Machida A., Kishimoto S., Ohnuma H., Miyamoto H., Baba K., Oda K., Nakamura T., Miyakawa M., Mayumi M. 1983; A hepatitis B surface antigen polypeptide (P31) with the receptor for polymerized human as well as chimpanzee albumins. Gastroenterology 85:268–274
    [Google Scholar]
  26. McKnight S. L., Kingsbury R. 1982; Transcriptional control signals of a eukaryotic protein-coding gene. Science 217:316–324
    [Google Scholar]
  27. Maguire H. F., Hoeffler J. P., Siddiqui A. 1991; HBV x protein alters the DNA binding specificity of CREB and ATF-2 by proteinprotein interactions. Science 252:842–844
    [Google Scholar]
  28. 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 on nuclear factor-KB and CCAAT/enhancer-binding protein-like cis-element. Journal of Biological Chemistry 266:13759–13763
    [Google Scholar]
  29. Mauxion F., Jamieson C., Yoshida M., Arai K., Sen R. 1991; Comparison of constitutive and inducible enhancement mediated by k B- related sequences - modulation of activity in B-cells by human T-cell leukemia virus type-I tax gene. Proceedings of the National Academy of Sciences USA: 882141–2145
    [Google Scholar]
  30. Meyer M., Caselmann W. H., Schlüter V., Schreck R., Hofschneider P. H., Baeuerle P. A. 1992; Hepatitis B virus transactivator MHBst: activation of NF- k B, selective inhibition by antioxidants and integral membrane localization. EMBO Journal 11:2991–3001
    [Google Scholar]
  31. Müuhlbauer E., Koch W. 1995; Differences in the target specificity of the transactivating factors MHBst and HBx of hepatitis B virus. Journal of General Virology 76:1033–1039
    [Google Scholar]
  32. Natoli G., Avantaggiati M. L., Balsano C., DeMarzio E., Collepardo D., Elfassi E., Levrero M. 1992; Characterization of the hepatitis B virus preS/S region encoded transcriptional transactivator. Virology 187:663–670
    [Google Scholar]
  33. Nose K., Shibanuma M., Kikuchi K., Kageyama H., Sakiyama S., Kuroki T. 1991; Transcriptional activation of early-response genes by hydrogen peroxide in a mouse osteoblastic cell line. European Journal of Biochemistry 201:99–106
    [Google Scholar]
  34. Raney A. K., Milich D. R., McLachlan A. 1991; Complex regulation of transcription from the hepatitis B virus major surface antigen promoter in human hepatoma cell lines. Journal of Virology 65:4805–4811
    [Google Scholar]
  35. Raney A. K., Le H. B., McLachlan A. 1992; Regulation of transcription from the hepatitis B virus major surface antigen promoter by the Sp1 transcription factor. Journal of Virology 66:6912–6921
    [Google Scholar]
  36. Schlüter V., Meyer M., Hofschneider P. H., Koshy R., Caselmann W. H. 1994; Integrated hepatitis B virus X and 3ʹ-truncated preS/S sequences derived from human hepatomas encode functionally active transactivators. Oncogene 9:3335–3344
    [Google Scholar]
  37. Schreck R., Rieber P., Baeuerle P. A. 1991; Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF- k B transcription factor and HIV1. EMBO Journal 10:2247–2258
    [Google Scholar]
  38. Schule R., Muller M., Kaltschmidt C., Renkawitz R. 1988; Many transcription factors interact synergistically with steroid receptors. Science 242:1418–1420
    [Google Scholar]
  39. Seto E., Mitchell P. J., Yen T. S. B. 1990; Transactivation by hepatitis B virus x protein depends on AP-2 and other transcription factors. Nature 344:72–74
    [Google Scholar]
  40. Shaul Y., Rutter W. J., Laub O. 1985; A human hepatitis B viral enhancer element. EMBO Journal 4:427–430
    [Google Scholar]
  41. Shaul Y., Ben-Levy R., De-Medina T. 1986; High affinity binding site for nuclear factor 1 next to the hepatitis B virus S gene promoter. EMBO Journal 5:1967–1971
    [Google Scholar]
  42. Siddiqui A., Jameel S., Mapoles J. E. 1987; Expression of the hepatitis B virus X gene in mammalian cells. Proceedings of the National Academy of Sciences USA: 842513–2517
    [Google Scholar]
  43. Trujillo M. A., Letovsky J., Maguire H. F., Babrerea M. L., Siddiqui A. 1991; Functional analysis of the liver-specific enhancer of hepatitis B virus. Proceedings of the National Academy of Sciences USA: 883797–3801
    [Google Scholar]
  44. Yee J. K. 1989; A liver-specific enhancer in the core promoter region of human hepatitis B virus. Science 246:658–661
    [Google Scholar]
  45. Yuh C. H., Chang Y. L., Ting L. P. 1992; Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus. Journal of Virology 66:4073–4084
    [Google Scholar]
  46. Zhang P., Raney A. K., McLachlan A. 1992; . Characterization ofthe hepatitis B virus X- and nucleocapsid-gene transcriptional regulatory element Virology 191:31–41
    [Google Scholar]
  47. Zhang P., Raney A. K., McLachlan A. 1993; Characterization of functional Sp1 transcription factor binding sites in the hepatitis B virus nucleocapsid promoter. Journal of Virology 67:1472–1481
    [Google Scholar]
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