Regulation of human papillomavirus type 16 DNA replication by E2, glucocorticoid hormone and epidermal growth factor Free

Abstract

The E1 and E2 proteins are the only human papillomavirus (HPV) proteins required for transient replication of plasmids containing the viral origin. The E2 gene products play key roles in both viral transcription and replication. In this study we have analysed in further detail the nature of the association between E1 and E2 using a series of E2 proteins mutated in conserved regions of the N- terminal domain. These proteins were tested for their ability to activate transcription and to stimulate viral DNA replication. Several of these mutants revealed that the two functions of E2 can be separated, and that they define three widely spaced regions of the N-terminal domain which are important for DNA replication, two of which retain E1- binding activity. This suggests that E2 may have a role in viral DNA replication other than simply localizing E1 to the origin of replication. Additional important elements for regulating viral gene expression have been shown to be glucocorticoid hormones and epidermal growth factor (EGF). We show here that they may also be involved in regulating viral DNA replication. Our studies show that the addition of glucocorticoid hormone significantly stimulates viral DNA replication. In contrast, addition of EGF results in modest repression of viral DNA replication. These results have important implications for the pathogenesis of HPV infection and suggest that the relative levels of E2, glucocorticoid hormone and EGF may significantly affect the outcome of an HPV infection.

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1997-08-01
2024-03-28
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References

  1. Androphy E. J., Lowy D. R., Schiller J. T. 1987; Bovine papillomavirus E2 trans-activating gene product binds to specific sites in the papillomavirus DNA. Nature 325:70–73
    [Google Scholar]
  2. 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]
  3. Bauknecht T., Angel P., Royer H. -D., zur Hausen H. 1992; Identification of a negative regulatory domain in the human papillomavirus type 18 promoter: interaction with the transcriptional repressor YY1. EMBO Journal 11:4607–4617
    [Google Scholar]
  4. Blitz I., Laimins L. A. 1991; The 68-kilodalton E1 protein of bovine papillomavirus is a DNA binding phosphoprotein which associates with the E2 transcription factor in vitro. Journal of Virology 65: 649–656
    [Google Scholar]
  5. Bouvard V., Storey A., Pim D., Banks L. 1994a; Characterization of the human papillomavirus E2 protein: evidence of trans-activation and trans-repression in cervical keratinocytes. EMBO Journal 13:5451–5459
    [Google Scholar]
  6. Bouvard V., Matlashewski G., Gu Z. -M., Storey A., Banks L. 1994b; The human papillomavirus type 16 E5 gene cooperates with the E7 gene to stimulate proliferation of primary cells and increases viral gene expression. Virology 203:73–80
    [Google Scholar]
  7. Bream G. L., Ohmstede C. A., Phelps W. C. 1993; Characterization of the human papillomavirus type 11 E1 and E2 proteins expressed in insect cells. Journal of Virology 67: 2655–2663
    [Google Scholar]
  8. Cantley L. C., Auger K. R., Carpenter C., Duckworth B., Graziani A., Kapeller R., Soltoff S. 1991; Oncogenes and signal transduction. Cell 64:281–302
    [Google Scholar]
  9. 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 tumor promoters through AP-1 binding sites. Nucleic Acids Research 18:763–769
    [Google Scholar]
  10. Chiang C. -M., Ustav A., Stenlund A., Ho T. F., Broker T. R., Chow L. T. 1992; Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins. Proceedings of the National Academy of Sciences USA: 89 5799–5803
    [Google Scholar]
  11. 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 AP1 participate in epithelial cell-specific transcription. Journal of Virology 65:5933–5943
    [Google Scholar]
  12. Cripe T. P., Haugen T. H., Turk J. P., Tabatabai F., Schmid P. G., Dürst M., Gissmann L., Roman A., Turek L. 1987; Transcriptional regulation of the human papillomavirus-16 E6-E7 promoter by a keratinocyte-dependent enhancer, and by a viral E2 transactivator and repressor gene products: implications for cervical carcinogenesis. EMBO Journal 6:3745–3753
    [Google Scholar]
  13. Gilbert D. M., Cohen S. N. 1987; Bovine papilloma virus plasmids replicate randomly in mouse fibroblasts throughout S phase of the cell cycle. Cell 50:59–68
    [Google Scholar]
  14. Giri I., Yaniv M. 1988; Structural and mutational analysis of E2 transactivating proteins of papillomaviruses reveals three distinct functional domains. EMBO Journal 7:2823–2829
    [Google Scholar]
  15. 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]
  16. Gloss B., Bernard H. -U., Klock G. 1987; The upstream regulatory region of the human papillomavirus type 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]
  17. Hibma M. H., Raj K., Ely S. J., Stanley M., Crawford L. 1995; The interaction between human papillomavirus type 16 E1 and E2 proteins is blocked by an antibody to the N-terminal region of E2. European Journal of Biochemistry 229:517–525
    [Google Scholar]
  18. Hirt B. 1967; Selective extraction of polyoma DNA from infected mouse cell cultures. Journal of Molecular Biology 26:365–369
    [Google Scholar]
  19. Hughes F. J., Romanos M. A. 1993; E1 protein of human papillomavirus is a DNA helicase/ATPase. Nucleic Acids Research 21:5817–5823
    [Google Scholar]
  20. Lambert P. F., Spalholz B. A., Howley P. M. 1987; A transcriptional repressor encoded by BPV-1 shares a common carboxy-terminal domain with the E2 transactivator. Cell 50:69–78
    [Google Scholar]
  21. Law M. F., Lowy D. R., Dvoretzky I., Howley P. M. 1981; Mouse cells transformed by bovine papillomavirus contain only extrachromosomal viral DNA sequences. Proceedings of the National Academy of Sciences USA: 782727–2731
    [Google Scholar]
  22. Lees E., Osborn K., Banks L., Crawford L. 1990; Transformation of primary BRK cells by human papillomavirus type 16 and EJ-ras is increased by overexpression of the viral E2 protein. Journal of General Virology 71:183–193
    [Google Scholar]
  23. Matsukura T., Koi S., Sugase M. 1989; Both episomal and integrated forms of human papillomavirus type 16 are involved in invasive cervical cancers. Virology 172:63–72
    [Google Scholar]
  24. Phelps W. C., Howley P. M. 1987; Transcriptional transactivation by the human papillomavirus type 16 E2 gene product. Journal of Virology 61:1630–1638
    [Google Scholar]
  25. Piccini A., Storey A., Massimi P., Banks L. 1995; Mutations in the human papillomavirus type 16 E2 protein identify multiple regions of the protein involved in binding to E1. Journal of General Virology 76:2909–2913
    [Google Scholar]
  26. Ravnan J. -B., Gilbert G. M., TenHagen K. G., Cohen S. N. 1992; Random choice replication of extrachromosomal bovine papillomavirus (BPV) molecules in heterogeneous clonally-derived BPV-infected cell lines. Journal of Virology 66:6946–6952
    [Google Scholar]
  27. Remm M., Brain R., Jenkins J. R. 1992; The E2 binding sites determine the efficiency of replication for the origin of human papillomavirus type 18. Nucleic Acids Research 20:6015–6021
    [Google Scholar]
  28. Sakai H., Toshiharu Y., Benson J. D., Dowhanick J. J., Howley P. M. 1996; Targeted mutagenesis of the human papillomavirus type 16 E2 transactivation domain reveals separable transcriptional activation and replication functions. Journal of Virology 70:1602–1611
    [Google Scholar]
  29. Schwarz E., Freese U. K., Gissmann L., Mayer W., Roggenbuck B., Stremlau A., zur Hausen H. 1985; Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature 314:111–114
    [Google Scholar]
  30. Seo Y. -S., Müller F., Lusky M., Hurwitz J. 1993; Bovine papillomavirus (BPV)-encoded E1 protein contains multiple activities required for DNA replication. Proceedings of the National Academy of Sciences USA: 90702–706
    [Google Scholar]
  31. Sibbet G. J., Campo M. S. 1990; Multiple interactions between cellular factors and the non-coding region of human papillomavirus type 16. Journal of General Virology 71:2699–2707
    [Google Scholar]
  32. Storey A., Piccini A., Massimi P., Bouvard V., Banks L. 1995; Mutations in the human papillomavirus type 16 E2 protein identify a region of the protein involved in binding to E1 protein. Journal of General Virology 76:819–826
    [Google Scholar]
  33. Sun S., Thorner L., Lentz M., MacPherson P., Botchan M. 1990; Identification of a 68-kilodalton nuclear ATP-binding phosphoprotein encoded by bovine papillomavirus type 1. Journal of Virology 64:5093–5105
    [Google Scholar]
  34. Tsai M. -J., O’Malley B. W. 1994; Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annual Review of Biochemistry 63:451–486
    [Google Scholar]
  35. 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]
  36. Ustav M., Stenlund A. 1991; Transient replication ofBPV-1 requires two viral polypeptides encoded by the E1 and E2 open reading frames. EMBO Journal 10:505–509
    [Google Scholar]
  37. Wilson V. G., Ludes-Meyers J. 1991; A bovine papillomavirus E1- related protein binds specifically to bovine papillomavirus DNA. Journal of Virology 65: 5314–5322
    [Google Scholar]
  38. Yang L., Li R., Mohr L. J., Clark R., Botchan M. R. 1991; Activation of BPV-1 replication in vitro by the transcription factor E2. Nature 353:628–632
    [Google Scholar]
  39. Zuo F., Mertz J. E. 1995; Simian virus 40 late gene expression is regulated by members of the steroid/thyroid hormone receptor superfamily. Proceedings of the National Academy of Sciences USA: 928586–8590
    [Google Scholar]
  40. zur Hausen H., Schneider A. 1987; The role of papillomaviruses in human anogenital cancer. In The Papovaviridae: The Papillomaviruses pp 245–263 Howley P. M., Salzman N. Edited by New York: Plenum Press;
    [Google Scholar]
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