Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1996 Sep;70(9):6060–6066. doi: 10.1128/jvi.70.9.6060-6066.1996

Interactions of the transcription factors MIBP1 and RFX1 with the EP element of the hepatitis B virus enhancer.

M Blake 1, J Niklinski 1, M Zajac-Kaye 1
PMCID: PMC190627  PMID: 8709229

Abstract

We previously demonstrated that MIBP1 and RFX1 polypeptides associate in vivo to form a complex that binds to the MIF-1 element in the c-myc gene and the major histocompatibility complex class II X-box recognition sequence. We now show that the EP element, a key regulatory sequence within hepatitis B virus enhancer I, also associates with MIBP1 and RFX1. Using polyclonal antisera directed against either oligonucleotide-purified MIBP1 or a peptide derived from the major histocompatibility complex class II promoter-binding protein RFX1, we showed that MIBP1 and RFX1 are both present in the DNA-protein complexes at the EP site. In addition, while the EP element can act cooperatively with several adjacent elements to transactivate hepatitis B virus expression, we demonstrated that the EP site alone can repress transcription of simian virus 40 promoter in a position- and orientation-independent manner, suggesting a silencer function in hepatocarcinoma cells.

Full Text

The Full Text of this article is available as a PDF (1.5 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Antonucci T. K., Rutter W. J. Hepatitis B virus (HBV) promoters are regulated by the HBV enhancer in a tissue-specific manner. J Virol. 1989 Feb;63(2):579–583. doi: 10.1128/jvi.63.2.579-583.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arcinas M., Sizer K. C., Boxer L. M. Activation of c-myc expression by c-Abl is independent of both the DNA binding function of c-Abl and the c-myc EP site. J Biol Chem. 1994 Aug 26;269(34):21919–21924. [PubMed] [Google Scholar]
  3. Beasley R. P., Hwang L. Y., Lin C. C., Chien C. S. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet. 1981 Nov 21;2(8256):1129–1133. doi: 10.1016/s0140-6736(81)90585-7. [DOI] [PubMed] [Google Scholar]
  4. Ben-Levy R., Faktor O., Berger I., Shaul Y. Cellular factors that interact with the hepatitis B virus enhancer. Mol Cell Biol. 1989 Apr;9(4):1804–1809. doi: 10.1128/mcb.9.4.1804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen M., Hieng S., Qian X., Costa R., Ou J. H. Regulation of hepatitis B virus ENI enhancer activity by hepatocyte-enriched transcription factor HNF3. Virology. 1994 Nov 15;205(1):127–132. doi: 10.1006/viro.1994.1627. [DOI] [PubMed] [Google Scholar]
  6. David E., Garcia A. D., Hearing P. Interaction of EF-C/RFX-1 with the inverted repeat of viral enhancer regions is required for transactivation. J Biol Chem. 1995 Apr 7;270(14):8353–8360. doi: 10.1074/jbc.270.14.8353. [DOI] [PubMed] [Google Scholar]
  7. Dikstein R., Faktor O., Ben-Levy R., Shaul Y. Functional organization of the hepatitis B virus enhancer. Mol Cell Biol. 1990 Jul;10(7):3683–3689. doi: 10.1128/mcb.10.7.3683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dikstein R., Heffetz D., Ben-Neriah Y., Shaul Y. c-abl has a sequence-specific enhancer binding activity. Cell. 1992 May 29;69(5):751–757. doi: 10.1016/0092-8674(92)90287-m. [DOI] [PubMed] [Google Scholar]
  9. Fromental C., Kanno M., Nomiyama H., Chambon P. Cooperativity and hierarchical levels of functional organization in the SV40 enhancer. Cell. 1988 Sep 23;54(7):943–953. doi: 10.1016/0092-8674(88)90109-2. [DOI] [PubMed] [Google Scholar]
  10. Ganem D., Varmus H. E. The molecular biology of the hepatitis B viruses. Annu Rev Biochem. 1987;56:651–693. doi: 10.1146/annurev.bi.56.070187.003251. [DOI] [PubMed] [Google Scholar]
  11. Garcia A. D., Ostapchuk P., Hearing P. Functional interaction of nuclear factors EF-C, HNF-4, and RXR alpha with hepatitis B virus enhancer I. J Virol. 1993 Jul;67(7):3940–3950. doi: 10.1128/jvi.67.7.3940-3950.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Guo W. T., Bell K. D., Ou J. H. Characterization of the hepatitis B virus EnhI enhancer and X promoter complex. J Virol. 1991 Dec;65(12):6686–6692. doi: 10.1128/jvi.65.12.6686-6692.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Guo W., Chen M., Yen T. S., Ou J. H. Hepatocyte-specific expression of the hepatitis B virus core promoter depends on both positive and negative regulation. Mol Cell Biol. 1993 Jan;13(1):443–448. doi: 10.1128/mcb.13.1.443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gustin K., Shapiro M., Lee W., Burk R. D. 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. 1993 Apr;193(2):653–660. doi: 10.1006/viro.1993.1173. [DOI] [PubMed] [Google Scholar]
  16. Herr W., Clarke J. The SV40 enhancer is composed of multiple functional elements that can compensate for one another. Cell. 1986 May 9;45(3):461–470. doi: 10.1016/0092-8674(86)90332-6. [DOI] [PubMed] [Google Scholar]
  17. Hsu I. C., Tokiwa T., Bennett W., Metcalf R. A., Welsh J. A., Sun T., Harris C. C. p53 gene mutation and integrated hepatitis B viral DNA sequences in human liver cancer cell lines. Carcinogenesis. 1993 May;14(5):987–992. doi: 10.1093/carcin/14.5.987. [DOI] [PubMed] [Google Scholar]
  18. Hu K. Q., Siddiqui A. Regulation of the hepatitis B virus gene expression by the enhancer element I. Virology. 1991 Apr;181(2):721–726. doi: 10.1016/0042-6822(91)90906-r. [DOI] [PubMed] [Google Scholar]
  19. Huan B., Kosovsky M. J., Siddiqui A. Retinoid X receptor alpha transactivates the hepatitis B virus enhancer 1 element by forming a heterodimeric complex with the peroxisome proliferator-activated receptor. J Virol. 1995 Jan;69(1):547–551. doi: 10.1128/jvi.69.1.547-551.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Huan B., Siddiqui A. Retinoid X receptor RXR alpha binds to and trans-activates the hepatitis B virus enhancer. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9059–9063. doi: 10.1073/pnas.89.19.9059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Liaw Y. F., Tai D. I., Chu C. M., Chen T. J. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology. 1988 May-Jun;8(3):493–496. doi: 10.1002/hep.1840080310. [DOI] [PubMed] [Google Scholar]
  22. Mangelsdorf D. J., Ong E. S., Dyck J. A., Evans R. M. Nuclear receptor that identifies a novel retinoic acid response pathway. Nature. 1990 May 17;345(6272):224–229. doi: 10.1038/345224a0. [DOI] [PubMed] [Google Scholar]
  23. Ondek B., Gloss L., Herr W. The SV40 enhancer contains two distinct levels of organization. Nature. 1988 May 5;333(6168):40–45. doi: 10.1038/333040a0. [DOI] [PubMed] [Google Scholar]
  24. Ori A., Shaul Y. Hepatitis B virus enhancer binds and is activated by the Hepatocyte nuclear factor 3. Virology. 1995 Feb 20;207(1):98–106. doi: 10.1006/viro.1995.1055. [DOI] [PubMed] [Google Scholar]
  25. Ostapchuk P., Diffley J. F., Bruder J. T., Stillman B., Levine A. J., Hearing P. Interaction of a nuclear factor with the polyomavirus enhancer region. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8550–8554. doi: 10.1073/pnas.83.22.8550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ostapchuk P., Scheirle G., Hearing P. Binding of nuclear factor EF-C to a functional domain of the hepatitis B virus enhancer region. Mol Cell Biol. 1989 Jul;9(7):2787–2797. doi: 10.1128/mcb.9.7.2787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Patel N. U., Jameel S., Isom H., Siddiqui A. Interactions between nuclear factors and the hepatitis B virus enhancer. J Virol. 1989 Dec;63(12):5293–5301. doi: 10.1128/jvi.63.12.5293-5301.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Pegoraro L., Matera L., Ritz J., Levis A., Palumbo A., Biagini G. Establishment of a Ph1-positive human cell line (BV173). J Natl Cancer Inst. 1983 Mar;70(3):447–453. [PubMed] [Google Scholar]
  29. Reinhold W., Emens L., Itkes A., Blake M., Ichinose I., Zajac-Kaye M. The myc intron-binding polypeptide associates with RFX1 in vivo and binds to the major histocompatibility complex class II promoter region, to the hepatitis B virus enhancer, and to regulatory regions of several distinct viral genes. Mol Cell Biol. 1995 Jun;15(6):3041–3048. doi: 10.1128/mcb.15.6.3041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Reith W., Barras E., Satola S., Kobr M., Reinhart D., Sanchez C. H., Mach B. Cloning of the major histocompatibility complex class II promoter binding protein affected in a hereditary defect in class II gene regulation. Proc Natl Acad Sci U S A. 1989 Jun;86(11):4200–4204. doi: 10.1073/pnas.86.11.4200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Reith W., Herrero-Sanchez C., Kobr M., Silacci P., Berte C., Barras E., Fey S., Mach B. MHC class II regulatory factor RFX has a novel DNA-binding domain and a functionally independent dimerization domain. Genes Dev. 1990 Sep;4(9):1528–1540. doi: 10.1101/gad.4.9.1528. [DOI] [PubMed] [Google Scholar]
  32. Schreiber E., Matthias P., Müller M. M., Schaffner W. Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989 Aug 11;17(15):6419–6419. doi: 10.1093/nar/17.15.6419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Siegrist C. A., Durand B., Emery P., David E., Hearing P., Mach B., Reith W. RFX1 is identical to enhancer factor C and functions as a transactivator of the hepatitis B virus enhancer. Mol Cell Biol. 1993 Oct;13(10):6375–6384. doi: 10.1128/mcb.13.10.6375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sladek F. M., Zhong W. M., Lai E., Darnell J. E., Jr Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev. 1990 Dec;4(12B):2353–2365. doi: 10.1101/gad.4.12b.2353. [DOI] [PubMed] [Google Scholar]
  35. Su H., Yee J. K. Regulation of hepatitis B virus gene expression by its two enhancers. Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2708–2712. doi: 10.1073/pnas.89.7.2708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Szmuness W. Hepatocellular carcinoma and the hepatitis B virus: evidence for a causal association. Prog Med Virol. 1978;24:40–69. [PubMed] [Google Scholar]
  37. Trujillo M. A., Letovsky J., Maguire H. F., Lopez-Cabrera M., Siddiqui A. Functional analysis of a liver-specific enhancer of the hepatitis B virus. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3797–3801. doi: 10.1073/pnas.88.9.3797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Wang L. H., Ing N. H., Tsai S. Y., O'Malley B. W., Tsai M. J. The COUP-TFs compose a family of functionally related transcription factors. Gene Expr. 1991;1(3):207–216. [PMC free article] [PubMed] [Google Scholar]
  39. Yu B. W., Ichinose I., Bonham M. A., Zajac-Kaye M. Somatic mutations in c-myc intron I cluster in discrete domains that define protein binding sequences. J Biol Chem. 1993 Sep 15;268(26):19586–19592. [PubMed] [Google Scholar]
  40. Zajac-Kaye M., Gelmann E. P., Levens D. A point mutation in the c-myc locus of a Burkitt lymphoma abolishes binding of a nuclear protein. Science. 1988 Jun 24;240(4860):1776–1780. doi: 10.1126/science.2454510. [DOI] [PubMed] [Google Scholar]
  41. Zajac-Kaye M., Levens D. Phosphorylation-dependent binding of a 138-kDa myc intron factor to a regulatory element in the first intron of the c-myc gene. J Biol Chem. 1990 Mar 15;265(8):4547–4551. [PubMed] [Google Scholar]
  42. Zhang X. Y., Jabrane-Ferrat N., Asiedu C. K., Samac S., Peterlin B. M., Ehrlich M. The major histocompatibility complex class II promoter-binding protein RFX (NF-X) is a methylated DNA-binding protein. Mol Cell Biol. 1993 Nov;13(11):6810–6818. doi: 10.1128/mcb.13.11.6810. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Zhang X. Y., Supakar P. C., Wu K. Z., Ehrlich K. C., Ehrlich M. An MDBP site in the first intron of the human c-myc gene. Cancer Res. 1990 Nov 1;50(21):6865–6869. [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES