Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1997 Oct;71(10):8029–8034. doi: 10.1128/jvi.71.10.8029-8034.1997

Competitive binding of viral E2 protein and mammalian core-binding factor to transcriptional control sequences of human papillomavirus type 8 and bovine papillomavirus type 1.

H M Schmidt 1, G Steger 1, H Pfister 1
PMCID: PMC192167  PMID: 9311900

Abstract

The promoter P7535 of human papillomavirus type 8 and the promoter P7185 of bovine papillomavirus type 1 are negatively regulated by viral E2 proteins via the promoter proximal binding sites P2 and BS1, respectively. Mutations of these E2 binding sites can reduce basal promoter activity. This suggests binding of a transcription-stimulating factor and may indicate that repression by E2 is due to competitive binding of viral and cellular proteins. A computer search revealed putative binding sites for core-binding factor (CBF; also referred to as PEA2, PEBP2, or AML), overlapping with P2 and BS1. Binding of recombinant CBF proteins to these sites was confirmed by band shift analysis. Competition of CBF and E2 protein for DNA binding was shown for both human papillomavirus type 8 and bovine papillomavirus type 1. The importance of CBF-E2 competition in E2-mediated repression could be demonstrated by comparing the E2 effect on P7185 activity in two cell lines containing different amounts of endogenous CBF. In cells with large amounts of CBF, E2 repressed P7185 wild-type constructs to the basal promoter activity of a mutant (50%) that could not bind this protein any more. In contrast, in a cell line containing small amounts of CBF, the promoter activities of constructs with wild-type and mutated CBF binding sites hardly differed and specific repression by E2 was not detectable.

Full Text

The Full Text of this article is available as a PDF (981.3 KB).

Selected References

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

  1. Asselineau D., Bernard B. A., Bailly C., Darmon M., Pruniéras M. Human epidermis reconstructed by culture: is it "normal"? J Invest Dermatol. 1986 Feb;86(2):181–186. doi: 10.1111/1523-1747.ep12284237. [DOI] [PubMed] [Google Scholar]
  2. Bae S. C., Ogawa E., Maruyama M., Oka H., Satake M., Shigesada K., Jenkins N. A., Gilbert D. J., Copeland N. G., Ito Y. PEBP2 alpha B/mouse AML1 consists of multiple isoforms that possess differential transactivation potentials. Mol Cell Biol. 1994 May;14(5):3242–3252. doi: 10.1128/mcb.14.5.3242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Banerjee C., Hiebert S. W., Stein J. L., Lian J. B., Stein G. S. An AML-1 consensus sequence binds an osteoblast-specific complex and transcriptionally activates the osteocalcin gene. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4968–4973. doi: 10.1073/pnas.93.10.4968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dong X. P., Stubenrauch F., Beyer-Finkler E., Pfister H. Prevalence of deletions of YY1-binding sites in episomal HPV 16 DNA from cervical cancers. Int J Cancer. 1994 Sep 15;58(6):803–808. doi: 10.1002/ijc.2910580609. [DOI] [PubMed] [Google Scholar]
  5. Furukawa K., Yamaguchi Y., Ogawa E., Shigesada K., Satake M., Ito Y. A ubiquitous repressor interacting with an F9 cell-specific silencer and its functional suppression by differentiated cell-specific positive factors. Cell Growth Differ. 1990 Mar;1(3):135–147. [PubMed] [Google Scholar]
  6. Giese K., Kingsley C., Kirshner J. R., Grosschedl R. Assembly and function of a TCR alpha enhancer complex is dependent on LEF-1-induced DNA bending and multiple protein-protein interactions. Genes Dev. 1995 Apr 15;9(8):995–1008. doi: 10.1101/gad.9.8.995. [DOI] [PubMed] [Google Scholar]
  7. Hiebert S. W., Sun W., Davis J. N., Golub T., Shurtleff S., Buijs A., Downing J. R., Grosveld G., Roussell M. F., Gilliland D. G. The t(12;21) translocation converts AML-1B from an activator to a repressor of transcription. Mol Cell Biol. 1996 Apr;16(4):1349–1355. doi: 10.1128/mcb.16.4.1349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Horn S., Pfister H., Fuchs P. G. Constitutive transcriptional activator of Epidermodysplasia verruciformis-associated human papillomavirus 8. Virology. 1993 Oct;196(2):674–681. doi: 10.1006/viro.1993.1524. [DOI] [PubMed] [Google Scholar]
  9. Jackson M. E., Campo M. S. Both viral E2 protein and the cellular factor PEBP2 regulate transcription via E2 consensus sites within the bovine papillomavirus type 4 long control region. J Virol. 1995 Oct;69(10):6038–6046. doi: 10.1128/jvi.69.10.6038-6046.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Kamachi Y., Ogawa E., Asano M., Ishida S., Murakami Y., Satake M., Ito Y., Shigesada K. Purification of a mouse nuclear factor that binds to both the A and B cores of the polyomavirus enhancer. J Virol. 1990 Oct;64(10):4808–4819. doi: 10.1128/jvi.64.10.4808-4819.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Levine M., Manley J. L. Transcriptional repression of eukaryotic promoters. Cell. 1989 Nov 3;59(3):405–408. doi: 10.1016/0092-8674(89)90024-x. [DOI] [PubMed] [Google Scholar]
  12. Melnikova I. N., Crute B. E., Wang S., Speck N. A. Sequence specificity of the core-binding factor. J Virol. 1993 Apr;67(4):2408–2411. doi: 10.1128/jvi.67.4.2408-2411.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Meyers C., Frattini M. G., Hudson J. B., Laimins L. A. Biosynthesis of human papillomavirus from a continuous cell line upon epithelial differentiation. Science. 1992 Aug 14;257(5072):971–973. doi: 10.1126/science.1323879. [DOI] [PubMed] [Google Scholar]
  14. Meyers S., Downing J. R., Hiebert S. W. Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: the runt homology domain is required for DNA binding and protein-protein interactions. Mol Cell Biol. 1993 Oct;13(10):6336–6345. doi: 10.1128/mcb.13.10.6336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Meyers S., Lenny N., Hiebert S. W. The t(8;21) fusion protein interferes with AML-1B-dependent transcriptional activation. Mol Cell Biol. 1995 Apr;15(4):1974–1982. doi: 10.1128/mcb.15.4.1974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ogawa E., Inuzuka M., Maruyama M., Satake M., Naito-Fujimoto M., Ito Y., Shigesada K. Molecular cloning and characterization of PEBP2 beta, the heterodimeric partner of a novel Drosophila runt-related DNA binding protein PEBP2 alpha. Virology. 1993 May;194(1):314–331. doi: 10.1006/viro.1993.1262. [DOI] [PubMed] [Google Scholar]
  17. Ogawa E., Maruyama M., Kagoshima H., Inuzuka M., Lu J., Satake M., Shigesada K., Ito Y. PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6859–6863. doi: 10.1073/pnas.90.14.6859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Purdie K. J., Sexton C. J., Proby C. M., Glover M. T., Williams A. T., Stables J. N., Leigh I. M. Malignant transformation of cutaneous lesions in renal allograft patients: a role for human papillomavirus. Cancer Res. 1993 Nov 1;53(21):5328–5333. [PubMed] [Google Scholar]
  19. Reh H., Pfister H. Human papillomavirus type 8 contains cis-active positive and negative transcriptional control sequences. J Gen Virol. 1990 Oct;71(Pt 10):2457–2462. doi: 10.1099/0022-1317-71-10-2457. [DOI] [PubMed] [Google Scholar]
  20. Rutberg S. E., Dolan L. R., Ronai Z. PEBP2--a modulator of polyoma DNA replication. DNA Cell Biol. 1994 Aug;13(8):865–874. doi: 10.1089/dna.1994.13.865. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. Steger G., Corbach S. Dose-dependent regulation of the early promoter of human papillomavirus type 18 by the viral E2 protein. J Virol. 1997 Jan;71(1):50–58. doi: 10.1128/jvi.71.1.50-58.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Steger G., Ham J., Lefebvre O., Yaniv M. The bovine papillomavirus 1 E2 protein contains two activation domains: one that interacts with TBP and another that functions after TBP binding. EMBO J. 1995 Jan 16;14(2):329–340. doi: 10.1002/j.1460-2075.1995.tb07007.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Stenlund A., Botchan M. R. The E2 trans-activator can act as a repressor by interfering with a cellular transcription factor. Genes Dev. 1990 Jan;4(1):123–136. doi: 10.1101/gad.4.1.123. [DOI] [PubMed] [Google Scholar]
  25. Stubenrauch F., Leigh I. M., Pfister H. E2 represses the late gene promoter of human papillomavirus type 8 at high concentrations by interfering with cellular factors. J Virol. 1996 Jan;70(1):119–126. doi: 10.1128/jvi.70.1.119-126.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Stubenrauch F., Malejczyk J., Fuchs P. G., Pfister H. Late promoter of human papillomavirus type 8 and its regulation. J Virol. 1992 Jun;66(6):3485–3493. doi: 10.1128/jvi.66.6.3485-3493.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Stubenrauch F., Pfister H. Low-affinity E2-binding site mediates downmodulation of E2 transactivation of the human papillomavirus type 8 late promoter. J Virol. 1994 Nov;68(11):6959–6966. doi: 10.1128/jvi.68.11.6959-6966.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Takahashi A., Satake M., Yamaguchi-Iwai Y., Bae S. C., Lu J., Maruyama M., Zhang Y. W., Oka H., Arai N., Arai K. Positive and negative regulation of granulocyte-macrophage colony-stimulating factor promoter activity by AML1-related transcription factor, PEBP2. Blood. 1995 Jul 15;86(2):607–616. [PubMed] [Google Scholar]
  29. Vande Pol S. B., Howley P. M. A bovine papillomavirus constitutive enhancer is negatively regulated by the E2 repressor through competitive binding for a cellular factor. J Virol. 1990 Nov;64(11):5420–5429. doi: 10.1128/jvi.64.11.5420-5429.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wang Q., Stacy T., Miller J. D., Lewis A. F., Gu T. L., Huang X., Bushweller J. H., Bories J. C., Alt F. W., Ryan G. The CBFbeta subunit is essential for CBFalpha2 (AML1) function in vivo. Cell. 1996 Nov 15;87(4):697–708. doi: 10.1016/s0092-8674(00)81389-6. [DOI] [PubMed] [Google Scholar]
  31. Wang S., Wang Q., Crute B. E., Melnikova I. N., Keller S. R., Speck N. A. Cloning and characterization of subunits of the T-cell receptor and murine leukemia virus enhancer core-binding factor. Mol Cell Biol. 1993 Jun;13(6):3324–3339. doi: 10.1128/mcb.13.6.3324. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Wasylyk B., Imler J. L., Chatton B., Schatz C., Wasylyk C. Negative and positive factors determine the activity of the polyoma virus enhancer alpha domain in undifferentiated and differentiated cell types. Proc Natl Acad Sci U S A. 1988 Nov;85(21):7952–7956. doi: 10.1073/pnas.85.21.7952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wotton D., Ghysdael J., Wang S., Speck N. A., Owen M. J. Cooperative binding of Ets-1 and core binding factor to DNA. Mol Cell Biol. 1994 Jan;14(1):840–850. doi: 10.1128/mcb.14.1.840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Yang Y. C., Okayama H., Howley P. M. Bovine papillomavirus contains multiple transforming genes. Proc Natl Acad Sci U S A. 1985 Feb;82(4):1030–1034. doi: 10.1073/pnas.82.4.1030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Zaiman A. L., Lenz J. Transcriptional activation of a retrovirus enhancer by CBF (AML1) requires a second factor: evidence for cooperativity with c-Myb. J Virol. 1996 Aug;70(8):5618–5629. doi: 10.1128/jvi.70.8.5618-5629.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Zaiman A. L., Lewis A. F., Crute B. E., Speck N. A., Lenz J. Transcriptional activity of core binding factor-alpha (AML1) and beta subunits on murine leukemia virus enhancer cores. J Virol. 1995 May;69(5):2898–2906. doi: 10.1128/jvi.69.5.2898-2906.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES