1887

Abstract

Human papillomavirus type 16 (HPV-16) is a DNA tumour virus that has been implicated in the development of cervical cancer. The HPV-16 E2 protein binds to four sites that are present upstream of the viral P97 promoter and regulates transcription of the E6 and E7 oncogenes. Here, it is shown that cellular transcription factors bind to two of these E2 sites. One cellular E2 site-binding factor, which is here named CEF-1, binds tightly to E2 site 1. CEF-2, an unrelated cellular E2 site-binding factor, binds tightly to E2 site 3. Transient transfection studies performed in the absence of the E2 protein showed that mutations that blocked the binding of CEF-1 to E2 site 1 or CEF-2 to E2 site 3 significantly reduced P97 promoter activity. Further characterization of CEF-1 indicated that this factor has not previously been identified and that CEF-1 and E2 competed for binding at E2 site 1.

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1999-08-01
2024-11-08
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References

  1. Baker C. C., Phelps W. C., Lindgren V., Braun M. J., Gonda M. A., Howley P. M. 1987; Structural and transcriptional analysis of human papillomavirus type 16 sequences in cervical carcinoma cell lines. Journal of Virology 61:962–971
    [Google Scholar]
  2. Bauknecht T., See R. H., Shi Y. 1996; A novel C/EBP β–YY1 complex controls the cell-type-specific activity of the human papillomavirus type 18 upstream regulatory region. Journal of Virology 70:7695–7705
    [Google Scholar]
  3. Bouvard V., Storey A., Pim D., Banks L. 1994; Characterization of the human papillomavirus E2 protein: evidence of trans -activation and trans -repression in cervical keratinocytes. EMBO Journal 13:5451–5459
    [Google Scholar]
  4. Chan W.-K., Klock G., Bernard H.-U. 1989; Progesterone and glucocorticoid response elements occur in the long control regions of several human papillomaviruses involved in anogenital neoplasia. Journal of Virology 63:3261–3269
    [Google Scholar]
  5. Chan W.-K., Chong T., Bernard H.-U., Klock G. 1990; Transcription of the transforming genes of the oncogenic human papillomavirus-16 is stimulated by the tumor promoters through AP1 binding sites. Nucleic Acids Research 18:763–769
    [Google Scholar]
  6. Chong T., Chan W.-K., Bernard H.-U. 1990; Transcriptional activation of human papillomavirus 16 by nuclear factor I, AP1, steroid receptors and a possibly novel transcription factor, PVF: a model for the composition of genital papillomavirus enhancers. Nucleic Acids Research 18:465–470
    [Google Scholar]
  7. Chong T., Apt D., Gloss B., Isa M., Bernard H.-U. 1991; The enhancer of human papillomavirus type 16: binding sites for the ubiquitous transcription factors oct-1, NFA, TEF-2, NF1, and AP-1 participate in epithelial cell-specific transcription. Journal of Virology 65:5933–5943
    [Google Scholar]
  8. Cripe T. P., Haugen T. H., Turk J. P., Tabatabai F., Schmid P. G.III., Dürst M., Gissmann L., Roman A., Turek L. P. 1987; Transcriptional regulation of the human papillomavirus-16 E6-E7 promoter by a keratinocyte-dependent enhancer, and by viral E2 trans -activator and repressor gene products: implications for cervical carcinogenesis. EMBO Journal 6:3745–3753
    [Google Scholar]
  9. Cuthill S., Sibbet G. J., Campo M. S. 1993; Characterization of a nuclear factor, papilloma enhancer binding factor-1, that binds the long control region of human papillomavirus type 16 and contributes to enhancer activity. Molecular Carcinogenesis 8:96–104
    [Google Scholar]
  10. Demeret C., Desaintes C., Yaniv M., Thierry F. 1997; Different mechanisms contribute to the E2-mediated transcriptional repression of human papillomavirus type 18 viral oncogenes. Journal of Virology 71:9343–9349
    [Google Scholar]
  11. Dignam J. D., Lebovitz R. M., Roeder R. G. 1983; Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Research 11:1475–1489
    [Google Scholar]
  12. Dong X.-P., Stubenrauch F., Beyer-Finkler E., Pfister H. 1994; Prevalence of deletions of YY1-binding sites in episomal HPV 16 DNA from cervical cancers. International Journal of Cancer 58:803–808
    [Google Scholar]
  13. Dorn A., Benoist C., Mathis D. 1989; New B-lymphocyte-specific enhancer-binding protein. Molecular and Cellular Biology 9:312–320
    [Google Scholar]
  14. Dostatni N., Lambert P. F., Sousa R., Ham J., Howley P. M., Yaniv M. 1991; The functional BPV-1 E2 trans-activating protein can act as a repressor by preventing formation of the initiation complex. Genes & Development 5:1657–1671
    [Google Scholar]
  15. Dürst M., Gissmann L., Ikenberg H., zur Hausen H. 1983; A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proceedings of the National Academy of Sciences, USA 80:3812–3815
    [Google Scholar]
  16. Dürst M., Kleinheinz A., Hotz M., Gissmann L. 1985; The physical state of human papillomavirus type 16 DNA in benign and malignant genital tumours. Journal of General Virology 66:1515–1522
    [Google Scholar]
  17. Dyson N., Howley P. M., Münger K., Harlow E. 1989; The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 243:934–937
    [Google Scholar]
  18. Gloss B., Bernard H.-U. 1990; The E6/E7 promoter of human papillomavirus type 16 is activated in the absence of E2 proteins by a sequence-aberrant Sp1 distal element. Journal of Virology 64:5577–5584
    [Google Scholar]
  19. Gloss B., Bernard H.-U., Seedorf K., Klock G. 1987; The upstream regulatory region of the human papilloma virus-16 contains an E2 protein-independent enhancer which is specific for cervical carcinoma cells and regulated by glucocorticoid hormones. EMBO Journal 6:3735–3743
    [Google Scholar]
  20. Ham J., Steger G., Yaniv M. 1994; Cooperativity in vivo between the E2 transactivator and the TATA box binding protein depends on core promoter structure. EMBO Journal 13:147–157
    [Google Scholar]
  21. Hawley-Nelson P., Vousden K. H., Hubbert N. L., Lowy D. R., Schiller J. T. 1989; HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO Journal 8:3905–3910
    [Google Scholar]
  22. Ishiji T., Lace M. J., Parkkinen S., Anderson R. D., Haugen R. H., Cripe T. P., Xiao J. H., Davidson I., Chambon P., Turek L. P. 1992; Transcriptional enhancer factor (TEF)-1 and its cell-specific co-activator activate human papillomavirus-16 E6 and E7 oncogene transcription in keratinocytes and cervical carcinoma cells. EMBO Journal 11:2271–2281
    [Google Scholar]
  23. Jackson M. E., Campo M. S. 1995; Both viral E2 protein and the cellular factor PEBP2 regulate transcription via E2 consensus sites within the bovine papillomavirus type 4 long control region. Journal of Virology 69:6038–6046
    [Google Scholar]
  24. Kovelman R., Bilter G. K., Glezer E., Tsou A. Y., Barbosa M. S. 1996; Enhanced transcriptional activation by E2 proteins from the oncogenic human papillomaviruses. Journal of Virology 70:7549–7560
    [Google Scholar]
  25. Kyo S., Inoue M., Nishio Y., Nakanishi K., Akira S., Inoue H., Yutsudo M., Tanizawa O., Hakura A. 1993; NF-IL6 represses early gene expression of human papillomavirus type 16 through binding to the noncoding region. Journal of Virology 67:1058–1066
    [Google Scholar]
  26. May M., Grassmann K., Pfister H., Fuchs P. G. 1994a; Transcriptional silencer of the human papillomavirus type 8 late promoter interacts alternatively with the viral trans activator E2 or with a cellular factor. Journal of Virology 68:3612–3619
    [Google Scholar]
  27. May M., Dong X. P., Beyer-Finkler E., Stubenrauch F., Fuchs P. G., Pfister H. 1994b; The E6/E7 promoter of extrachromosomal HPV16 DNA in cervical cancers escapes from cellular repression by mutation of target sequences for YY1. EMBO Journal 13:1460–1466
    [Google Scholar]
  28. Mohr I. J., Clark R., Sun S., Androphy E. J., MacPherson P., Botchan M. R. 1990; Targeting the E1 replication protein to the papillomavirus origin of replication by complex formation with the E2 transactivator. Science 250:1694–1699
    [Google Scholar]
  29. Münger K., Phelps W. C., Bubb V., Howley P. M., Schlegel R. 1989; The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. Journal of Virology 63:4417–4421
    [Google Scholar]
  30. O’Connor M., Bernard H.-U. 1995; Oct-1 activates the epithelial-specific enhancer of human papillomavirus type 16 via a synergistic interaction with NFI at a conserved composite regulatory element. Virology 207:77–88
    [Google Scholar]
  31. Ogawa E., Maruyama M., Kagoshima H., Inuzuka M., Lu J., Satake M., Shigesada K., Ito Y. 1993; PEBP2/PEA2 represents a family of transcription factors homologous to the products of the Drosophila runt gene and the human AML1 gene. Proceedings of the National Academy of Sciences, USA 90:6859–6863
    [Google Scholar]
  32. Peto R., zur Hausen H. (editors) 1986 Viral Etiology of Cervical Cancer. Banbury Report 21 Cold Spring Harbor, NY: Cold Spring Harbor Laboratory;
  33. Phelps W. C., Howley P. M. 1987; Transcriptional trans -activation by the human papillomavirus type 16 E2 gene product. Journal of Virology 61:1630–1638
    [Google Scholar]
  34. Romanczuk H., Thierry F., Howley P. M. 1990; Mutational analysis of cis elements involved in E2 modulation of human papillomavirus type 16 P97 and type 18 P105 promoters. Journal of Virology 64:2849–2859
    [Google Scholar]
  35. Sanchez-Perez A.-M., Soriano S., Clarke A. R., Gaston K. 1997; Disruption of the human papillomavirus type 16 E2 gene protects cervical carcinoma cells from E2F-induced apoptosis. Journal of General Virology 78:3009–3018
    [Google Scholar]
  36. Sanders C. M., Maitland N. J. 1994; Kinetic and equilibrium binding studies of the human papillomavirus type-16 transcription regulatory protein E2 interacting with core enhancer elements. Nucleic Acids Research 22:4890–4897
    [Google Scholar]
  37. Smotkin D., Wettstein F. O. 1986; Transcription of human papillomavirus type 16 early genes in a cervical cancer and a cancer-derived cell line and identification of the E7 protein. Proceedings of the National Academy of Sciences, USA 83:4680–4684
    [Google Scholar]
  38. Smotkin D., Prokoph H., Wettstein F. O. 1989; Oncogenic and nononcogenic human genital papillomaviruses generate the E7 mRNA by different mechanisms. Journal of Virology 63:1441–1447
    [Google Scholar]
  39. Stenlund A., Botchan M. R. 1990; The E2 trans-activator can act as a repressor by interfering with a cellular transcription factor. Genes & Development 4:123–136
    [Google Scholar]
  40. Stubenrauch F., Leigh I. M., Pfister H. 1996; E2 represses the late gene promoter of human papillomavirus type 8 at high concentrations by interfering with cellular factors. Journal of Virology 70:119–126
    [Google Scholar]
  41. Tan S.-H., Gloss B., Bernard H.-U. 1992; During negative regulation of the human papillomavirus-16 E6 promoter, the viral E2 protein can displace Sp1 from a proximal promoter element. Nucleic Acids Research 20:251–256
    [Google Scholar]
  42. Tan S.-H., Leong L. E.-C., Walker P. A., Bernard H.-U. 1994; The human papillomavirus type 16 E2 transcription factor binds with low cooperativity to two flanking sites and represses the E6 promoter through displacement of Sp1 and TFIID. Journal of Virology 68:6411–6420
    [Google Scholar]
  43. Thain A., Webster K., Emery D., Clarke A. R., Gaston K. 1997; DNA binding and bending by the human papillomavirus type 16 E2 protein. Recognition of an extended binding site. Journal of Biological Chemistry 272:8236–8242
    [Google Scholar]
  44. Ushikai M., Lace M. J., Yamakawa Y., Kono M., Anson J., Ishiji T., Parkkinen S., Wicker N., Valentine M.-E., Davidson I., Turek L. P., Haugen T. H. 1994; trans activation by the full-length E2 proteins of human papillomavirus type 16 and bovine papillomavirus type 1 in vitro and in vivo : cooperation with activation domains of cellular transcription factors. Journal of Virology 68:6655–6666
    [Google Scholar]
  45. van Ranst M., Tachezy R., Burk R. D. 1996; Human papillomaviruses: a never-ending story?. In Papillomavirus Reviews: Current Research on Papillomaviruses pp 1–19 Edited by Lacey C. Leeds: Leeds University Press;
    [Google Scholar]
  46. Vande Pol S. B., Howley P. M. 1990; A bovine papillomavirus constitutive enhancer is negatively regulated by the E2 repressor through competitive binding for a cellular factor. Journal of Virology 64:5420–5429
    [Google Scholar]
  47. Watanabe S., Kanda T., Yoshiike K. 1989; Human papillomavirus type 16 transformation of primary human embryonic fibroblasts requires expression of open reading frames E6 and E7. Journal of Virology 63:965–969
    [Google Scholar]
  48. Werness B. A., Levine A. J., Howley P. M. 1990; Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248:76–79
    [Google Scholar]
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