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. 1992 Apr;66(4):2346–2358. doi: 10.1128/jvi.66.4.2346-2358.1992

The bovine papillomavirus constitutive enhancer is essential for viral transformation, DNA replication, and the maintenance of latency.

S B Vande Pol 1, P M Howley 1
PMCID: PMC289030  PMID: 1312634

Abstract

Bovine papillomavirus type 1 (BPV-1) has served as the prototype papillomavirus for the study of viral transcription, DNA replication, and latency. However, no cis essential transcription control regions which are necessary for both transformation and replication of BPV-1 or any other papillomavirus have yet been defined. We have found that BPV-1 mutants with deletions in the long control region were defective for transformation and replication, with the essential region in the 5' long control region corresponding to the previously defined BPV-1 constitutive enhancer (S. B. Vande Pol and P. M. Howley, J. Virol. 64:5420-5429, 1990). BPV-1 mutants deleted of the constitutive enhancer could be complemented in trans by the full-length virally encoded E2 transactivator and replication factor (E2TA) and in cis by the simian virus 40 enhancer. The constitutive enhancer induced the production of E2TA by activating all the major viral early promoters upstream of the E2 open reading frame. Complementation experiments using a temperature-sensitive E2TA mutant indicated that the constitutive enhancer was necessary for the maintenance of viral DNA replication within latently infected cells and implied that viral transcription under the regulation of the constitutive enhancer may be controlled during the cell cycle. The constitutive enhancer is a master regulatory control region for establishing and maintaining BPV-1 latency, and its characteristics reveal some analogies with cell type-specific enhancer elements recognized in the human papillomaviruses.

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Selected References

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

  1. Ahola H., Stenlund A., Moreno-López J., Pettersson U. Promoters and processing sites within the transforming region of bovine papillomavirus type 1. J Virol. 1987 Jul;61(7):2240–2244. doi: 10.1128/jvi.61.7.2240-2244.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Androphy E. J., Lowy D. R., Schiller J. T. Bovine papillomavirus E2 trans-activating gene product binds to specific sites in papillomavirus DNA. Nature. 1987 Jan 1;325(6099):70–73. doi: 10.1038/325070a0. [DOI] [PubMed] [Google Scholar]
  3. Baker C. C., Howley P. M. Differential promoter utilization by the bovine papillomavirus in transformed cells and productively infected wart tissues. EMBO J. 1987 Apr;6(4):1027–1035. doi: 10.1002/j.1460-2075.1987.tb04855.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bernard B. A., Bailly C., Lenoir M. C., Darmon M., Thierry F., Yaniv M. The human papillomavirus type 18 (HPV18) E2 gene product is a repressor of the HPV18 regulatory region in human keratinocytes. J Virol. 1989 Oct;63(10):4317–4324. doi: 10.1128/jvi.63.10.4317-4324.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Birnboim H. C., Doly J. A rapid alkaline extraction procedure for screening recombinant plasmid DNA. Nucleic Acids Res. 1979 Nov 24;7(6):1513–1523. doi: 10.1093/nar/7.6.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blitz I. L., Laimins L. A. The 68-kilodalton E1 protein of bovine papillomavirus is a DNA binding phosphoprotein which associates with the E2 transcriptional activator in vitro. J Virol. 1991 Feb;65(2):649–656. doi: 10.1128/jvi.65.2.649-656.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Burnett S., Ström A. C., Jareborg N., Alderborn A., Dillner J., Moreno-Lopez J., Pettersson U., Kiessling U. Induction of bovine papillomavirus E2 gene expression and early region transcription by cell growth arrest: correlation with viral DNA amplification and evidence for differential promoter induction. J Virol. 1990 Nov;64(11):5529–5541. doi: 10.1128/jvi.64.11.5529-5541.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Campo M. S., Spandidos D. A., Lang J., Wilkie N. M. Transcriptional control signals in the genome of bovine papillomavirus type 1. Nature. 1983 May 5;303(5912):77–80. doi: 10.1038/303077a0. [DOI] [PubMed] [Google Scholar]
  9. Chin M. T., Broker T. R., Chow L. T. Identification of a novel constitutive enhancer element and an associated binding protein: implications for human papillomavirus type 11 enhancer regulation. J Virol. 1989 Jul;63(7):2967–2976. doi: 10.1128/jvi.63.7.2967-2976.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chin M. T., Hirochika R., Hirochika H., Broker T. R., Chow L. T. Regulation of human papillomavirus type 11 enhancer and E6 promoter by activating and repressing proteins from the E2 open reading frame: functional and biochemical studies. J Virol. 1988 Aug;62(8):2994–3002. doi: 10.1128/jvi.62.8.2994-3002.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  12. Choe J., Vaillancourt P., Stenlund A., Botchan M. Bovine papillomavirus type 1 encodes two forms of a transcriptional repressor: structural and functional analysis of new viral cDNAs. J Virol. 1989 Apr;63(4):1743–1755. doi: 10.1128/jvi.63.4.1743-1755.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cripe T. P., Haugen T. H., Turk J. P., Tabatabai F., Schmid P. G., 3rd, Dürst M., Gissmann L., Roman A., Turek L. P. 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 J. 1987 Dec 1;6(12):3745–3753. doi: 10.1002/j.1460-2075.1987.tb02709.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. DiMaio D., Guralski D., Schiller J. T. Translation of open reading frame E5 of bovine papillomavirus is required for its transforming activity. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1797–1801. doi: 10.1073/pnas.83.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. DiMaio D., Settleman J. Bovine papillomavirus mutant temperature sensitive for transformation, replication and transactivation. EMBO J. 1988 Apr;7(4):1197–1204. doi: 10.1002/j.1460-2075.1988.tb02931.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dvoretzky I., Shober R., Chattopadhyay S. K., Lowy D. R. A quantitative in vitro focus assay for bovine papilloma virus. Virology. 1980 Jun;103(2):369–375. doi: 10.1016/0042-6822(80)90195-6. [DOI] [PubMed] [Google Scholar]
  17. Garcia-Carranca A., Thierry F., Yaniv M. Interplay of viral and cellular proteins along the long control region of human papillomavirus type 18. J Virol. 1988 Nov;62(11):4321–4330. doi: 10.1128/jvi.62.11.4321-4330.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Gius D., Grossman S., Bedell M. A., Laimins L. A. Inducible and constitutive enhancer domains in the noncoding region of human papillomavirus type 18. J Virol. 1988 Mar;62(3):665–672. doi: 10.1128/jvi.62.3.665-672.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gloss B., Bernard H. U., Seedorf K., Klock G. 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 J. 1987 Dec 1;6(12):3735–3743. doi: 10.1002/j.1460-2075.1987.tb02708.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Haugen T. H., Cripe T. P., Ginder G. D., Karin M., Turek L. P. Trans-activation of an upstream early gene promoter of bovine papilloma virus-1 by a product of the viral E2 gene. EMBO J. 1987 Jan;6(1):145–152. doi: 10.1002/j.1460-2075.1987.tb04732.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hermonat P. L., Spalholz B. A., Howley P. M. The bovine papillomavirus P2443 promoter is E2 trans-responsive: evidence for E2 autoregulation. EMBO J. 1988 Sep;7(9):2815–2822. doi: 10.1002/j.1460-2075.1988.tb03137.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Howley P. M., Schenborn E. T., Lund E., Byrne J. C., Dahlberg J. E. The bovine papillomavirus distal "enhancer" is not cis essential for transformation or for plasmid maintenance. Mol Cell Biol. 1985 Nov;5(11):3310–3315. doi: 10.1128/mcb.5.11.3310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lambert P. F., Baker C. C., Howley P. M. The genetics of bovine papillomavirus type 1. Annu Rev Genet. 1988;22:235–258. doi: 10.1146/annurev.ge.22.120188.001315. [DOI] [PubMed] [Google Scholar]
  24. Lambert P. F., Howley P. M. Bovine papillomavirus type 1 E1 replication-defective mutants are altered in their transcriptional regulation. J Virol. 1988 Nov;62(11):4009–4015. doi: 10.1128/jvi.62.11.4009-4015.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lambert P. F., Spalholz B. A., Howley P. M. A transcriptional repressor encoded by BPV-1 shares a common carboxy-terminal domain with the E2 transactivator. Cell. 1987 Jul 3;50(1):69–78. doi: 10.1016/0092-8674(87)90663-5. [DOI] [PubMed] [Google Scholar]
  26. Law M. F., Lowy D. R., Dvoretzky I., Howley P. M. Mouse cells transformed by bovine papillomavirus contain only extrachromosomal viral DNA sequences. Proc Natl Acad Sci U S A. 1981 May;78(5):2727–2731. doi: 10.1073/pnas.78.5.2727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Li R., Knight J. D., Jackson S. P., Tjian R., Botchan M. R. Direct interaction between Sp1 and the BPV enhancer E2 protein mediates synergistic activation of transcription. Cell. 1991 May 3;65(3):493–505. doi: 10.1016/0092-8674(91)90467-d. [DOI] [PubMed] [Google Scholar]
  28. Lowy D. R., Dvoretzky I., Shober R., Law M. F., Engel L., Howley P. M. In vitro tumorigenic transformation by a defined sub-genomic fragment of bovine papilloma virus DNA. Nature. 1980 Sep 4;287(5777):72–74. doi: 10.1038/287072a0. [DOI] [PubMed] [Google Scholar]
  29. Lusky M., Botchan M. R. Characterization of the bovine papilloma virus plasmid maintenance sequences. Cell. 1984 Feb;36(2):391–401. doi: 10.1016/0092-8674(84)90232-0. [DOI] [PubMed] [Google Scholar]
  30. McBride A. A., Byrne J. C., Howley P. M. E2 polypeptides encoded by bovine papillomavirus type 1 form dimers through the common carboxyl-terminal domain: transactivation is mediated by the conserved amino-terminal domain. Proc Natl Acad Sci U S A. 1989 Jan;86(2):510–514. doi: 10.1073/pnas.86.2.510. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. McBride A. A., Schlegel R., Howley P. M. The carboxy-terminal domain shared by the bovine papillomavirus E2 transactivator and repressor proteins contains a specific DNA binding activity. EMBO J. 1988 Feb;7(2):533–539. doi: 10.1002/j.1460-2075.1988.tb02842.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Mohr I. J., Clark R., Sun S., Androphy E. J., MacPherson P., Botchan M. R. Targeting the E1 replication protein to the papillomavirus origin of replication by complex formation with the E2 transactivator. Science. 1990 Dec 21;250(4988):1694–1699. doi: 10.1126/science.2176744. [DOI] [PubMed] [Google Scholar]
  33. Moskaluk C., Bastia D. The E2 "gene" of bovine papillomavirus encodes an enhancer-binding protein. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1215–1218. doi: 10.1073/pnas.84.5.1215. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Phelps W. C., Howley P. M. Transcriptional trans-activation by the human papillomavirus type 16 E2 gene product. J Virol. 1987 May;61(5):1630–1638. doi: 10.1128/jvi.61.5.1630-1638.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Prakash S. S., Horwitz B. H., Zibello T., Settleman J., DiMaio D. Bovine papillomavirus E2 gene regulates expression of the viral E5 transforming gene. J Virol. 1988 Oct;62(10):3608–3613. doi: 10.1128/jvi.62.10.3608-3613.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rabson M. S., Yee C., Yang Y. C., Howley P. M. Bovine papillomavirus type 1 3' early region transformation and plasmid maintenance functions. J Virol. 1986 Nov;60(2):626–634. doi: 10.1128/jvi.60.2.626-634.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Romanczuk H., Thierry F., Howley P. M. Mutational analysis of cis elements involved in E2 modulation of human papillomavirus type 16 P97 and type 18 P105 promoters. J Virol. 1990 Jun;64(6):2849–2859. doi: 10.1128/jvi.64.6.2849-2859.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Sarver N., Byrne J. C., Howley P. M. Transformation and replication in mouse cells of a bovine papillomavirus--pML2 plasmid vector that can be rescued in bacteria. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7147–7151. doi: 10.1073/pnas.79.23.7147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sarver N., Rabson M. S., Yang Y. C., Byrne J. C., Howley P. M. Localization and analysis of bovine papillomavirus type 1 transforming functions. J Virol. 1984 Nov;52(2):377–388. doi: 10.1128/jvi.52.2.377-388.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Schiller J. T., Kleiner E., Androphy E. J., Lowy D. R., Pfister H. Identification of bovine papillomavirus E1 mutants with increased transforming and transcriptional activity. J Virol. 1989 Apr;63(4):1775–1782. doi: 10.1128/jvi.63.4.1775-1782.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Settleman J., Fazeli A., Malicki J., Horwitz B. H., DiMaio D. Genetic evidence that acute morphologic transformation, induction of cellular DNA synthesis, and focus formation are mediated by a single activity of the bovine papillomavirus E5 protein. Mol Cell Biol. 1989 Dec;9(12):5563–5572. doi: 10.1128/mcb.9.12.5563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sowden M., Harrison S., Ashfield R., Kingsman A. J., Kingsman S. M. Multiple cooperative interactions constrain BPV-1 E2 dependent activation of transcription. Nucleic Acids Res. 1989 Apr 25;17(8):2959–2972. doi: 10.1093/nar/17.8.2959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Spalholz B. A., Lambert P. F., Yee C. L., Howley P. M. Bovine papillomavirus transcriptional regulation: localization of the E2-responsive elements of the long control region. J Virol. 1987 Jul;61(7):2128–2137. doi: 10.1128/jvi.61.7.2128-2137.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Spalholz B. A., Vande Pol S. B., Howley P. M. Characterization of the cis elements involved in basal and E2-transactivated expression of the bovine papillomavirus P2443 promoter. J Virol. 1991 Feb;65(2):743–753. doi: 10.1128/jvi.65.2.743-753.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Spalholz B. A., Yang Y. C., Howley P. M. Transactivation of a bovine papilloma virus transcriptional regulatory element by the E2 gene product. Cell. 1985 Aug;42(1):183–191. doi: 10.1016/s0092-8674(85)80114-8. [DOI] [PubMed] [Google Scholar]
  46. 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]
  47. Stenlund A., Bream G. L., Botchan M. R. A promoter with an internal regulatory domain is part of the origin of replication in BPV-1. Science. 1987 Jun 26;236(4809):1666–1671. doi: 10.1126/science.3037693. [DOI] [PubMed] [Google Scholar]
  48. Szymanski P., Stenlund A. Regulation of early gene expression from the bovine papillomavirus genome in transiently transfected C127 cells. J Virol. 1991 Nov;65(11):5710–5720. doi: 10.1128/jvi.65.11.5710-5720.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Thierry F., Yaniv M. The BPV1-E2 trans-acting protein can be either an activator or a repressor of the HPV18 regulatory region. EMBO J. 1987 Nov;6(11):3391–3397. doi: 10.1002/j.1460-2075.1987.tb02662.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Ustav M., Stenlund A. Transient replication of BPV-1 requires two viral polypeptides encoded by the E1 and E2 open reading frames. EMBO J. 1991 Feb;10(2):449–457. doi: 10.1002/j.1460-2075.1991.tb07967.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Ustav M., Ustav E., Szymanski P., Stenlund A. Identification of the origin of replication of bovine papillomavirus and characterization of the viral origin recognition factor E1. EMBO J. 1991 Dec;10(13):4321–4329. doi: 10.1002/j.1460-2075.1991.tb05010.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. 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]
  53. 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]
  54. Yang Y. C., Spalholz B. A., Rabson M. S., Howley P. M. Dissociation of transforming and trans-activation functions for bovine papillomavirus type 1. Nature. 1985 Dec 12;318(6046):575–577. doi: 10.1038/318575a0. [DOI] [PubMed] [Google Scholar]

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