1887

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Volume 80, Issue 7

Many different papillomaviruses have low transcriptional activity in spite of strong epithelial specific enhancers Free

Abstract

Transcription of the E6-E7 genes of human papillomavirus type 11 (HPV-11), HPV-16 and HPV-18 is specific to epithelial cells. This mechanism originates from synergism between different transcription factors such as AP-1, NFI and Sp1, which occur in many different cell types, but whose activity is biased in favour of epithelial cells. In this study, the transcriptional regulation of 14 different papillomavirus types in the absence of the viral E2 transcription factor was compared. Genital HPV types, including high-risk, low-risk and common wart-associated HPVs, were found to have strong epithelial specific enhancers, irrespective of mucosal or skin target cell and pathology. Skin specific non-genital HPVs, like HPV-1 and HPV-8, as well as bovine papillomavirus type 4 (BPV-4), had much lower enhancer activity. Contiguous genomic segments including the enhancer and the E6 promoter of genital as well as non-genital papillomaviruses generally had very low transcriptional activities, presumably due to silencers between enhancer and promoter sequences. This generalization applies to all cell types tested in spite of significant quantitative differences between the cervical carcinoma-derived cell line HeLa, the skin-derived cell line HaCat, undifferentiated and differentiated primary keratinocytes. The only enhancer with activity in fibroblasts was identified in BPV-1, apparently a reflection of the broader target cell specificity of this virus. The low transcriptional activity of papillomaviruses most likely reflects the low gene expression required during most or even all parts of the life-cycle of these viruses.

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© Journal of General Virology 1999
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1999-07-01
2024-04-19
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References

  1. Andersen B., Hariri A., Pittelkow M. R., Rosenfeld M. G. 1997; Characterization of Skn-1a/i POU domain factors and linkage to papillomavirus gene expression. Journal of Biological Chemistry 272:15905–15913
     [Google Scholar]
  2. Apt D., Chong T., Liu Y., Bernard H. U. 1993; Nuclear factor I and epithelial cell-specific transcription of human papillomavirus type 16. Journal of Virology 67:4455–4463
     [Google Scholar]
  3. Apt D., Liu Y., Bernard H. U. 1994; Cloning and functional analysis of spliced isoforms of human nuclear factor I-X: interference with transcriptional activation by NFI/CTF in a cell type specific manner. Nucleic Acids Research 22:3825–3833
     [Google Scholar]
  4. Apt D., Watts R. M., Suske G., Bernard H. U. 1996; High Sp1/Sp3 ratios in epithelial cells during epithelial differentiation and cellular transformation correlate with the activation of the HPV-16 promoter. Virology 224:281–291
     [Google Scholar]
  5. Baker C. C., Howley P. M. 1987; Differential promoter utilization by the bovine papillomavirus in transformed cells and productively infected wart tissues. EMBO Journal 6:1027–1035
     [Google Scholar]
  6. 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]
  7. Bednarek P. H., Lee B. J., Gandhi S., Lee E., Phillips B. 1998; Novel binding sites for regulatory factors in the human papillomavirus type 18 enhancer and promoter identified by in vivo footprinting. Journal of Virology 72:708–716
     [Google Scholar]
  8. Bernard H. U., Chan S. Y. 1997; Animal papillomaviruses. In Human Papillomaviruses 1997 Compendium Edited by Myers G., Sverdrup F., Baker C., McBride A., Munger K., Bernard H. U., Meissner J. Los Alamos, NM, USA: Los Alamos National Laboratory;
     [Google Scholar]
  9. Boukamp P., Petrussevska R. T., Breitkreutz D., Hornung J., Markham A., Fusenig N. E. 1988; Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. Journal of Cell Biology 106:761–771
     [Google Scholar]
  10. Butz K., Hoppe-Seyler F. 1993; Transcriptional control of human papillomavirus (HPV) oncogene expression: composition of the HPV type 18 upstream regulatory region. Journal of Virology 67:6476–6486
     [Google Scholar]
  11. Chan S. Y., Delius H., Halpern A. L., Bernard H. U. 1995; Analysis of genomic sequences of 95 papillomavirus types: uniting typing, phylogeny, and taxonomy. Journal of Virology 69:3074–3083
     [Google Scholar]
  12. Cheng S., Schmidt-Grimminger D. C., Murant T., Broker T. R., Chow L. T. 1995; Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes & Development 9:2335–2349
     [Google Scholar]
  13. Chong T., Apt D., Gloss B., Isa M., Bernard H. U. 1991; The enhancer of human papillomavirus-16: binding sites for the ubiquitous transcription factors oct-1, NFA, TEF-2, NFI and AP1 participate in the epithelial specific transcription. Journal of Virology 65:5933–5943
     [Google Scholar]
  14. Cripe T. C., 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 viral E2 trans-activator and repressor gene products: implications for cervical carcinogenesis. EMBO Journal 6:3745–3753
     [Google Scholar]
  15. Dollard S. C., Broker T. R., Chow L. T. 1993; Regulation of the human papillomavirus type 11 E6 promoter by viral and host transcription factors in primary human keratinocytes. Journal of Virology 67:1721–1726
     [Google Scholar]
  16. Dong G., Broker T. R., Chow L. T. 1994; Human papillomavirus type 11 E2 proteins repress the homologous E6 promoter by interfering with the binding of host transcription factors to adjacent elements. Journal of Virology 68:1115–1127
     [Google Scholar]
  17. 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]
  18. Furth P. A., Choe W. T., Rex J. H., Byrne J. C., Baker C. C. 1994; Sequences homologous to 5′ splice sites are required for the inhibitory activity of papillomavirus late 3′ untranslated regions. Molecular and Cellular Biology 14:5278–5289
     [Google Scholar]
  19. Garcia-Carranca A., Thierry F., Yaniv M. 1988; Interplay of viral and cellular proteins along the long control region of human papillomavirus type 18. Journal of Virology 62:4321–4330
     [Google Scholar]
  20. 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]
  21. Gloss B., Bernard H. U., Seedorf K., Klock G. 1987; The upstream regulatory region of the human papillomavirus-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]
  22. Gloss B., Chong T., Bernard H. U. 1989a; Numerous nuclear proteins bind the long control region of human papillomavirus type 16: a subset of 6 of 23 DNAseI-protected segments coincides with the location of the cell–type-specific enhancer. Journal of Virology 63:1142–1152
     [Google Scholar]
  23. Gloss B., Yeo-Gloss M., Meisterernst M., Rogge L., Winnacker E. L., Bernard H. U. 1989b; Clusters of nuclear factor I binding sites identify enhancers of several papillomaviruses but alone are not sufficient for enhancer function. Nucleic Acids Research 17:3519–3533
     [Google Scholar]
  24. Hoppe-Seyler F., Butz K. 1992; Activation of human papillomavirus type 18 E6–E7 oncogene expression by transcription factor Sp1. Nucleic Acids Research 20:6701–6706
     [Google Scholar]
  25. Horn S., Pfister H., Fuchs P. G. 1993; Constitutive transcriptional activator of Epidermodysplasia verruciformis-associatedhumanpapilloma-virus 8. Virology 196:674–681
     [Google Scholar]
  26. Howley P. M. 1996; Papillomavirinae: the viruses and their replication. In Fields Virology 3rd edn Edited by Fields B. N., Knipe D. M., Howley P. M. Philadelphia, USA: Lippincott–Raven;
     [Google Scholar]
  27. Ishiji T., Lace M. J., Parkkinen S., Anderson R. D., Haugen T. H., Cripe T. P., Xiao J. H., Davidson I., Chambon P., Turek L. P. 1992; Transcriptional enhancer factor (TEF)-1 and its cell-specific coactivator activate human papillomavirus-16 E6 and E7 oncogene transcription in keratinocytes and cervical carcinoma cells. EMBO Journal 11:2271–2281
     [Google Scholar]
  28. 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]
  29. Jang S. I., Steinert P. M., Markova N. G. 1996; Activator protein 1 activity is involved in the regulation of the cell type-specific expression from the proximal promoter of the human profilaggrin gene. Journal of Biological Chemistry 271:24105–24114
     [Google Scholar]
  30. Kuo S.R., Liu J.S., Broker T.R., Chow L.T. 1994; Cell-free replication of the human papillomavirus DNA with homologous viral E1 and E2 proteins and human cell extracts. Journal of Biological Chemistry 269:24058–24065
     [Google Scholar]
  31. Kyo S., Tam A., Laimins L. A. 1995; Transcriptional activity of human papillomavirus type 31b enhancer is regulated through synergistic interaction of AP-1 with two novel cellular factors. Virology 211:184–197
     [Google Scholar]
  32. Kyo S., Klumpp D. J., Inoue M., Kanaya T., Laimins L. A. 1997; Expression of AP1 during cellular differentiation determines human papillomavirus E6/E7 expression in stratified epithelial cells. Journal of General Virology 78:401–411
     [Google Scholar]
  33. Lu J. Z., Sun Y. N., Rose R. C., Bonnez W., McCance D. J. 1993; Two E2 binding sites (E2BS) alone or one E2BS plus an A/T-rich region are minimal requirements for the replication of the human papillomavirus type 11 origin. Journal of Virology 67:7131–7139
     [Google Scholar]
  34. Lu B., Rothnagel J. A., Longley M. A., Tsai S. Y., Roop D. R. 1994; Differentiation-specific expression of human keratin 1 is mediated by a composite AP-1/steroid hormone element. Journal of Biological Chemistry 267:7443–7449
     [Google Scholar]
  35. Luckow B., Schütz G. 1987; CAT constructions with multiple unique restriction sites for the functional analysis of eukaryotic promoters and regulatory elements. Nucleic Acids Research 15:5490
     [Google Scholar]
  36. Mack D. H., Laimins L. A. 1991; A keratinocyte-specific transcription factor, KRF-1, interacts with AP-1 to activate expression of human papillomavirus type 18 in squamous epithelial cells. Proceedings of the National Academy of Sciences, USA 88:9102–9106
     [Google Scholar]
  37. May M., Dong X. P., Beyer-Finkler E., Stubenrauch F., Fuchs P. G., Pfister H. 1994; The E6/E7 promoter of extrachromosomal HPV16 DNA in cervical cancers escapes from cellular repression by mutation of target sequences for YY1. EMBO Journal 113:1460–1466
     [Google Scholar]
  38. Meyers C., Frattini M. G., Hudson J. B., Laimins L. A. 1992; Biosynthesis of human papillomavirus from a continuous cell line upon epithelial differentiation. Science 257:971–973
     [Google Scholar]
  39. Myers G., Sverdrup F., Baker C., McBride A., Munger K., Bernard H. U., Meissner J. 1997 Human Papillomaviruses 1997, part II, LCR pp 2–14 Los Alamos, NM, USA: Los Alamos National Laboratory;
     [Google Scholar]
  40. 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]
  41. O’Connor M., Chan S. Y., Bernard H. U. 1995; Transcription factor binding sites in the long control regions of genital HPVs. In Human Papillomaviruses 1995 Compendium, part III-A pp 21–40 Edited by Myers G., Bernard H. U., Delius H., Baker C., Icenogle J., Halpern A., Wheeler C. Los Alamos, NM, USA: Los Alamos National Laboratory;
     [Google Scholar]
  42. O’Connor M. J., Tan S. H., Tan C. H., Bernard H. U. 1996; YY1 represses human papillomavirus type 16 transcription by quenching AP-1 activity. Journal of Virology 70:6529–6539
     [Google Scholar]
  43. O’Connor M. J., Stünkel W., Zimmermann H., Koh C. H., Bernard H. U. 1998; A novel YY1-independent silencer represses the activity of the human papillomavirus type 16 enhancer. Journal of Virology 72:10083–10092
     [Google Scholar]
  44. Offord E. A., Chappuis P. O., Beard P. 1993; Different stability of AP1 proteins in human keratinocyte and fibroblast cells: possible role in the cell-type specific expression of human papillomavirus type 18 genes. Carcinogenesis 14:2447–2455
     [Google Scholar]
  45. Ozbun M. A., Meyers C. 1997; Characterization of late gene transcripts expressed during vegetative replication of human papillomavirus type 31b. Journal of Virology 71:5161–5172
     [Google Scholar]
  46. Parker J. N., Zhao W., Askins K. J., Broker T. R., Chow L. T. 1997; Mutational analysis of differentiation-dependent human papillomavirus type-18 enhancer elements in epitheila raft cultures of neonatal foreskin keratinocytes. Cell Growth & Differentiation 8:751–762
     [Google Scholar]
  47. Quinlan R. A., Schiller D. L., Hatzfeld M., Achtstatter T., Moll R., Jorcano J. L., Magin T. M., Franke W. W. 1985; Patterns of expression and organization of cytokeratin intermediate filaments. Annals of the New York Academy of Sciences 455:282–306
     [Google Scholar]
  48. Romanczuk H., Villa L. L., Schlegel R., Howley P. M. 1991; Theviral transcriptional regulatory region upstream of the E6 and E7 genes is a major determinant of the differential immortalization activities of humanpapillomavirustypes 16 and 18. JournalofVirology 65:2739–2744
     [Google Scholar]
  49. Sibbet G. J., Cuthill S., Campo S. M. 1995; The enhancer in the long control region of human papillomavirus type 16 is up-regulated by PEF-1 and down-regulated by Oct-1. Journal of Virology 69:4006–4011
     [Google Scholar]
  50. Spalholz B. A., Yang Y. C., Howley P. M. 1985; Transactivation of a bovine papilloma virus transcriptional regulatory element by the E2 gene product. Cell 42:183–191
     [Google Scholar]
  51. 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]
  52. Swift F. V., Bhat K., Younghusband H. B., Hamada H. 1987; Characterization of a cell type-specific enhancer found in the human papilloma virus type 18 genome. EMBO Journal 6:1339–1344
     [Google Scholar]
  53. Tan S. H., Leong L. E. C., Walker P., Bernard H. U. 1994; Thehuman 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]
  54. Tan S. H., Bartsch D., Schwarz E., Bernard H. U. 1998; Nuclear matrix attachment regions of human papillomavirus type 16 point toward conservation of these genomic elements in all genital papillomaviruses. Journal of Virology 72:3610–3622
     [Google Scholar]
  55. Tergaonkar V., Mythily D. V., Krishna S. 1997; Cytokeratin patterns of expression in human epithelial cell lines correlate with transcriptional activity of the human papillomavirus type 16 upstream regulatory region. Journal of General Virology 78:2601–2606
     [Google Scholar]
  56. Thierry F., Spyrou G., Yaniv M., Howley P. M. 1992; Two AP1 sites binding jun B are essential for human papillomavirus type 18 transcription in keratinocytes. Journal of Virology 66:3740–3748
     [Google Scholar]
  57. van de 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]
  58. van de Pol S. B., Howley P. M. 1992; The bovine papillomavirus constitutive enhancer is essential for viral transformation, DNA replication, and the maintenance of latency. Journal of Virology 66:2346–2358
     [Google Scholar]
  59. Wang H., Liu K., Yuan F., Berdichevsky L., Taichman L. B., Auborn K. 1996; C/EBPbeta is a negative regulator of human papillomavirus type 11 in keratinocytes. Journal of Virology 70:4839–4844
     [Google Scholar]
  60. Welter J. F., Eckert R. L. 1995; Differential expression of the fos and jun family members c–fos, fosB, Fra-1, Fra-2, c-jun, junB, and junD during human epidermal keratinocyte differentiation. Oncogene 11:2681–2687
     [Google Scholar]
  61. Wettstein F. O., Barbosa M. S., Nasseri M. 1987; Identification of the major cottontail rabbit papillomavirus late RNA cap site and mapping and quantitation of an E2 and minor E6 coding mRNA in papillomas and carcinomas. Virology 159:321–328
     [Google Scholar]
  62. Yukawa K., Butz K., Yasui T., Kikutani H., Hoppe-Seyler F. 1996; Regulation of human papillomavirus transcription by the differentiation-dependent epithelial factor Epoc-1/skn-1a. Journal of Virology 70:10–16
     [Google Scholar]
  63. Zhao W., Chow L. T., Broker T. R. 1997; Transcription activities of human papillomavirus type 11 E6 promoter-proximal elements in raft and submerged cultures of foreskin keratinocytes. Journal of Virology 71:8832–8840
     [Google Scholar]
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Many different papillomaviruses have low transcriptional activity in spite of strong epithelial specific enhancers
J. Gen. Virol. 80, 1715 (1999); https://doi.org/10.1099/0022-1317-80-7-1715
/content/journal/jgv/10.1099/0022-1317-80-7-1715
/content/journal/jgv/10.1099/0022-1317-80-7-1715
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