1887

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Volume 94, Issue 6

Cell-type-dependent activities of regulatory regions and E2 proteins derived from carcinogenic and non-carcinogenic human alphapapillomaviruses Free

Abstract

A large number of studies have revealed that persistent infections with certain human papillomavirus (HPV) types are necessary for the development of invasive cancer of the cervix. Recent studies have shown that not only do the major carcinogenic HPV types 16 and 18 encode E6 and E7 oncoproteins with immortalizing activity but also the very weakly or non-carcinogenic types 53, 66, 70 and 82. Currently, it is unknown whether transcriptional differences exist between these viruses that account for carcinogenicity . Therefore, we compared for the first time the activities of the upstream regulatory regions (URRs) that drive and expression derived from HPV16, -18, -31, -53, -66, -70 and -82 in the absence and presence of the viral E2 transcriptional regulator. URR activities in the absence of E2 varied widely and were further modulated by the cellular background. The co-expression of homologous E2 proteins resulted in repression of the URRs of only some HPV types and this varied with cell type. Activation by E2 proteins was less cell-type dependent but differed in an HPV-type-dependent manner. However, basal URR activity, repression of the URR by E2 and transcriptional activation by E2 did not correlate with HPV carcinogenicity . In summary, our data do not support the model that the transcriptional activity of human alphapapillomavirus types correlates with epidemiological risk classification.

  • Received:
  • Accepted:
  • Published Online:
© 2013 SGM
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2013-06-01
2024-05-09
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References

  1. Ammermann I., Bruckner M., Matthes F., Iftner T., Stubenrauch F. 2008; Inhibition of transcription and DNA replication by the papillomavirus E8^E2C protein is mediated by interaction with corepressor molecules. J Virol 82:5127–5136 [View Article][PubMed]
     [Google Scholar]
  2. Barbosa M. S., Vass W. C., Lowy D. R., Schiller J. T. 1991; In vitro biological activities of the E6 and E7 genes vary among human papillomaviruses of different oncogenic potential. J Virol 65:292–298[PubMed]
     [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 J 11:4607–4617[PubMed]
     [Google Scholar]
  4. Bernard H.-U., Burk R. D., Chen Z., van Doorslaer K., Hausen H., de Villiers E.-M. 2010; Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology 401:70–79 [View Article][PubMed]
     [Google Scholar]
  5. Burk R. D., Chen Z., Van Doorslaer K. 2009; Human papillomaviruses: genetic basis of carcinogenicity. Public Health Genomics 12:281–290 [View Article][PubMed]
     [Google Scholar]
  6. Butz K., Hoppe-Seyler F. 1993; Transcriptional control of human papillomavirus (HPV) oncogene expression: composition of the HPV type 18 upstream regulatory region. J Virol 67:6476–6486[PubMed]
     [Google Scholar]
  7. 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 Res 18:465–470 [View Article][PubMed]
     [Google Scholar]
  8. 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. J Virol 65:5933–5943[PubMed]
     [Google Scholar]
  9. Cripe T. P., Alderborn A., Anderson R. D., Parkkinen S., Bergman P., Haugen T. H., Pettersson U., Turek L. P. 1990; Transcriptional activation of the human papillomavirus-16 P97 promoter by an 88-nucleotide enhancer containing distinct cell-dependent and AP-1-responsive modules. New Biol 2:450–463[PubMed]
     [Google Scholar]
  10. de Sanjose S., Quint W. G., Alemany L., Geraets D. T., Klaustermeier J. E., Lloveras B., Tous S., Felix A., Bravo L. E. other authors 2010; Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol 11:1048–1056 [View Article][PubMed]
     [Google Scholar]
  11. Fertey J., Ammermann I., Winkler M., Stöger R., Iftner T., Stubenrauch F. 2010; Interaction of the papillomavirus E8^E2C protein with the cellular CHD6 protein contributes to transcriptional repression. J Virol 84:9505–9515 [View Article][PubMed]
     [Google Scholar]
  12. Fertey J., Hurst J., Straub E., Schenker A., Iftner T., Stubenrauch F. 2011; Growth inhibition of HeLa cells is a conserved feature of high-risk human papillomavirus E8^E2C proteins and can also be achieved by an artificial repressor protein. J Virol 85:2918–2926 [View Article][PubMed]
     [Google Scholar]
  13. 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. J Virol 64:5577–5584[PubMed]
     [Google Scholar]
  14. Halbert C. L., Demers G. W., Galloway D. A. 1992; The E6 and E7 genes of human papillomavirus type 6 have weak immortalizing activity in human epithelial cells. J Virol 66:2125–2134[PubMed]
     [Google Scholar]
  15. Hiller T., Poppelreuther S., Stubenrauch F., Iftner T. 2006; Comparative analysis of 19 genital human papillomavirus types with regard to p53 degradation, immortalization, phylogeny, and epidemiologic risk classification. Cancer Epidemiol Biomarkers Prev 15:1262–1267 [View Article][PubMed]
     [Google Scholar]
  16. Hoppe-Seyler F., Butz K. 1992; Activation of human papillomavirus type 18 E6-E7 oncogene expression by transcription factor Sp1. Nucleic Acids Res 20:6701–6706 [View Article][PubMed]
     [Google Scholar]
  17. Hoppe-Seyler F., Butz K., zur Hausen H. 1991; Repression of the human papillomavirus type 18 enhancer by the cellular transcription factor Oct-1. J Virol 65:5613–5618[PubMed]
     [Google Scholar]
  18. Howie H. L., Katzenellenbogen R. A., Galloway D. A. 2009; Papillomavirus E6 proteins. Virology 384:324–334 [View Article][PubMed]
     [Google Scholar]
  19. Hubert W. G. 2005; Variant upstream regulatory region sequences differentially regulate human papillomavirus type 16 DNA replication throughout the viral life cycle. J Virol 79:5914–5922 [View Article][PubMed]
     [Google Scholar]
  20. Hubert W. G., Kanaya T., Laimins L. A. 1999; DNA replication of human papillomavirus type 31 is modulated by elements of the upstream regulatory region that lie 5′ of the minimal origin. J Virol 73:1835–1845[PubMed]
     [Google Scholar]
  21. 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 co-activator activate human papillomavirus-16 E6 and E7 oncogene transcription in keratinocytes and cervical carcinoma cells. EMBO J 11:2271–2281[PubMed]
     [Google Scholar]
  22. Kämmer C., Warthorst U., Torrez-Martinez N., Wheeler C. M., Pfister H. 2000; Sequence analysis of the long control region of human papillomavirus type 16 variants and functional consequences for P97 promoter activity. J Gen Virol 81:1975–1981[PubMed]
     [Google Scholar]
  23. Kanaya T., Kyo S., Laimins L. A. 1997; The 5′ region of the human papillomavirus type 31 upstream regulatory region acts as an enhancer which augments viral early expression through the action of YY1. Virology 237:159–169 [View Article][PubMed]
     [Google Scholar]
  24. Kyo S., Tam A., Laimins L. A. 1995; Transcriptional activity of human papillomavirus type 31b enhancer is regulated through synergistic interaction of AP1 with two novel cellular factors. Virology 211:184–197 [View Article][PubMed]
     [Google Scholar]
  25. 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. Proc Natl Acad Sci U S A 88:9102–9106 [View Article][PubMed]
     [Google Scholar]
  26. 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 J 13:1460–1466[PubMed]
     [Google Scholar]
  27. McBride A. A., Romanczuk H., Howley P. M. 1991; The papillomavirus E2 regulatory proteins. J Biol Chem 266:18411–18414[PubMed]
     [Google Scholar]
  28. McLaughlin-Drubin M. E., Münger K. 2009; The human papillomavirus E7 oncoprotein. Virology 384:335–344 [View Article][PubMed]
     [Google Scholar]
  29. McPhillips M. G., Oliveira J. G., Spindler J. E., Mitra R., McBride A. A. 2006; Brd4 is required for E2-mediated transcriptional activation but not genome partitioning of all papillomaviruses. J Virol 80:9530–9543 [View Article][PubMed]
     [Google Scholar]
  30. Mesplède T., Gagnon D., Bergeron-Labrecque F., Azar I., Sénéchal H., Coutlée F., Archambault J. 2012; p53 degradation activity, expression, and subcellular localization of E6 proteins from 29 human papillomavirus genotypes. J Virol 86:94–107 [View Article][PubMed]
     [Google Scholar]
  31. Moody C. A., Laimins L. A. 2010; Human papillomavirus oncoproteins: pathways to transformation. Nat Rev Cancer 10:550–560 [View Article][PubMed]
     [Google Scholar]
  32. Muench P., Hiller T., Probst S., Florea A. M., Stubenrauch F., Iftner T. 2009; Binding of PDZ proteins to HPV E6 proteins does neither correlate with epidemiological risk classification nor with the immortalization of foreskin keratinocytes. Virology 387:380–387 [View Article][PubMed]
     [Google Scholar]
  33. Nindl I., Gottschling M., Stockfleth E. 2007; Human papillomaviruses and non-melanoma skin cancer: basic virology and clinical manifestations. Dis Markers 23:247–259[PubMed] [CrossRef]
     [Google Scholar]
  34. Ottinger M., Smith J. A., Schweiger M. R., Robbins D., Powell M. L., You J., Howley P. M. 2009; Cell-type specific transcriptional activities among different papillomavirus long control regions and their regulation by E2. Virology 395:161–171 [View Article][PubMed]
     [Google Scholar]
  35. Powell M. L., Smith J. A., Sowa M. E., Harper J. W., Iftner T., Stubenrauch F., Howley P. M. 2010; NCoR1 mediates papillomavirus E8^E2C transcriptional repression. J Virol 84:4451–4460 [View Article][PubMed]
     [Google Scholar]
  36. Romanczuk H., Villa L. L., Schlegel R., Howley P. M. 1991; The viral transcriptional regulatory region upstream of the E6 and E7 genes is a major determinant of the differential immortalization activities of human papillomavirus types 16 and 18. J Virol 65:2739–2744[PubMed]
     [Google Scholar]
  37. Schiffman M., Clifford G., Buonaguro F. M. 2009; Classification of weakly carcinogenic human papillomavirus types: addressing the limits of epidemiology at the borderline. Infect Agent Cancer 4:8 [View Article][PubMed]
     [Google Scholar]
  38. Schweiger M. R., You J., Howley P. M. 2006; Bromodomain protein 4 mediates the papillomavirus E2 transcriptional activation function. J Virol 80:4276–4285 [View Article][PubMed]
     [Google Scholar]
  39. Smith J. S., Lindsay L., Hoots B., Keys J., Franceschi S., Winer R., Clifford G. M. 2007; Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer 121:621–632 [View Article][PubMed]
     [Google Scholar]
  40. Smith J. A., White E. A., Sowa M. E., Powell M. L., Ottinger M., Harper J. W., Howley P. M. 2010; Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression. Proc Natl Acad Sci U S A 107:3752–3757 [View Article][PubMed]
     [Google Scholar]
  41. 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. Proc Natl Acad Sci U S A 83:4680–4684 [View Article][PubMed]
     [Google Scholar]
  42. Steger G., Corbach S. 1997; Dose-dependent regulation of the early promoter of human papillomavirus type 18 by the viral E2 protein. J Virol 71:50–58[PubMed]
     [Google Scholar]
  43. Stubenrauch F., Hummel M., Iftner T., Laimins L. A. 2000; The E8E2C protein, a negative regulator of viral transcription and replication, is required for extrachromosomal maintenance of human papillomavirus type 31 in keratinocytes. J Virol 74:1178–1186 [View Article][PubMed]
     [Google Scholar]
  44. Stubenrauch F., Zobel T., Iftner T. 2001; The E8 domain confers a novel long-distance transcriptional repression activity on the E8^E2C protein of high-risk human papillomavirus type 31. J Virol 75:4139–4149 [View Article][PubMed]
     [Google Scholar]
  45. Thierry F., Spyrou G., Yaniv M., Howley P. 1992; Two AP1 sites binding JunB are essential for human papillomavirus type 18 transcription in keratinocytes. J Virol 66:3740–3748[PubMed]
     [Google Scholar]
  46. Tota J. E., Chevarie-Davis M., Richardson L. A., Devries M., Franco E. L. 2011; Epidemiology and burden of HPV infection and related diseases: implications for prevention strategies. Prev Med 53:Suppl 1S12–S21 [View Article][PubMed]
     [Google Scholar]
  47. Walboomers J. M., Jacobs M. V., Manos M. M., Bosch F. X., Kummer J. A., Shah K. V., Snijders P. J., Peto J., Meijer C. J., Muñoz N. 1999; Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12–19 [View Article][PubMed]
     [Google Scholar]
  48. Wang W.-M., Wu S.-Y., Lee A.-Y., Chiang C.-M. 2011; Binding site specificity and factor redundancy in activator protein-1-driven human papillomavirus chromatin-dependent transcription. J Biol Chem 286:40974–40986 [View Article][PubMed]
     [Google Scholar]
  49. Wu S.-Y., Lee A.-Y., Hou S. Y., Kemper J. K., Erdjument-Bromage H., Tempst P., Chiang C.-M. 2006; Brd4 links chromatin targeting to HPV transcriptional silencing. Genes Dev 20:2383–2396 [View Article][PubMed]
     [Google Scholar]
  50. 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. J Virol 71:8832–8840[PubMed]
     [Google Scholar]
  51. zur Hausen H. 2002; Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2:342–350 [View Article][PubMed]
     [Google Scholar]
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Cell-type-dependent activities of regulatory regions and E2 proteins derived from carcinogenic and non-carcinogenic human alphapapillomaviruses
J. Gen. Virol. 94, 1343 (2013); https://doi.org/10.1099/vir.0.049072-0
/content/journal/jgv/10.1099/vir.0.049072-0
/content/journal/jgv/10.1099/vir.0.049072-0
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