1887

Abstract

Persistent infections of the uterine cervix with ‘high-risk’ human papillomavirus (HPV) are now recognized as necessary for the development of cervical cancer. Among them, HPV types 16 and 18 exhibit numerous variants associated with different risks for cervical cancer development. In this study, the questions of whether different HPV type 18 variants exhibit changes in early gene transcription and the molecular mechanisms underlying these differences were investigated. It was shown that, indeed, type 18 variants exhibited singular differences in E6 transcripts . Higher levels of the E6*I transcript were detected regularly in clones harbouring the African variant, as opposed to low levels of this transcript detected in clones containing the reference clone (Asian–Amerindian), where significantly higher levels of full-length E6 transcript were usually observed. As a direct consequence, higher levels of p53 protein were found in the presence of African E6, as opposed to the low levels of p53 observed with the Asian–Amerindian E6. These variations in consequence affected the levels of cellular proteins regulated by p53, such as Bax. Similar changes in the relative levels of E6 transcripts were observed when tumours containing type 18 E6 variants were analysed. The different ability of cells containing variant E6 genes to form tumours in nude mice was suggested by the fact that tumour volumes were considerably higher when cells expressed the Asian–Amerindian E6. Mutagenesis analysis of the reference clone showed that a C491A change reverts the phenotype. These results suggest that different splicing patterns of E6 within HPV type 18 variants may possibly have biological implications in viral tumorigenesis.

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2005-09-01
2019-11-21
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References

  1. Bernard, H. U., Chan, S. Y., Manos, M. M., Ong, C. K., Villa, L. L., Delius, H., Peyton, C. L., Bauer, H. M. & Wheeler, C. M. ( 1994; ). Identification and assessment of known and novel human papillomaviruses by polymerase chain reaction amplification, restriction fragment length polymorphisms, nucleotide sequence, and phylogenetic algorithms. J Infect Dis 170, 1077–1085.[CrossRef]
    [Google Scholar]
  2. Berumen, J., Ordoñez, R. M., Lazcano, E. & 7 other authors ( 2001; ). Asian-American variants of human papillomavirus 16 and risk for cervical cancer: a case–control study. J Natl Cancer Inst 93, 1325–1330.[CrossRef]
    [Google Scholar]
  3. Bosch, F. X., Lorincz, A., Muñoz, N., Meijer, C. J. L. M. & Shah, K. V. ( 2002; ). The causal relation between human papillomavirus and cervical cancer. J Clin Pathol 55, 244–265.[CrossRef]
    [Google Scholar]
  4. Brow, D. A. ( 2002; ). Allosteric cascade of spliceosome activation. Annu Rev Genet 36, 333–360.[CrossRef]
    [Google Scholar]
  5. Burger, R. A., Monk, B. J., Kurosaki, T., Anton-Culver, H., Vasilev, S. A., Berman, M. L. & Wilczynski, S. P. ( 1996; ). Human papillomavirus type 18: association with poor prognosis in early stage cervical cancer. J Natl Cancer Inst 88, 1361–1368.[CrossRef]
    [Google Scholar]
  6. Caelles, C., Helmberg, A. & Karin, M. ( 1994; ). p53-dependent apoptosis in the absence of transcriptional activation of p53-target genes. Nature 370, 220–223.[CrossRef]
    [Google Scholar]
  7. Chakrabarti, O., Veeraraghavalu, K., Tergaonkar, V., Liu, Y., Androphy, E. J., Stanley, M. A. & Krishna, S. ( 2004; ). Human papillomavirus type 16 E6 amino acid 83 variants enhance E6-mediated MAPK signaling and differentially regulate tumorigenesis by Notch signaling and oncogenic Ras. J Virol 78, 5934–5945.[CrossRef]
    [Google Scholar]
  8. Chen, X., Ko, L. J., Jayaraman, L. & Prives, C. ( 1996; ). p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells. Genes Dev 10, 2438–2451.[CrossRef]
    [Google Scholar]
  9. Chipuk, J. E. & Green, D. R. ( 2004; ). Cytoplasmic p53: Bax and forward. Cell Cycle 3, 429–431.
    [Google Scholar]
  10. Czegledy, J., Evander, M., Hernadi, Z., Gergely, L. & Wadell, G. ( 1994; ). Human papillomavirus type 18 E6* mRNA in primary tumors and pelvic lymph nodes of Hungarian patients with squamous cervical cancer. Int J Cancer 56, 182–186.[CrossRef]
    [Google Scholar]
  11. Dalstein, V., Riethmuller, D., Prétet, J.-L., Le Bail Carval, K., Sautière, J.-L., Carbillet, J.-P., Kantelip, B., Schaal, J.-P. & Mougin, C. ( 2003; ). Persistence and load of high-risk HPV are predictors for development of high-grade cervical lesions: a longitudinal French cohort study. Int J Cancer 106, 396–403.[CrossRef]
    [Google Scholar]
  12. De Boer, M. A., Peters, L. A. W., Aziz, M. F., Siregar, B., Cornain, S., Vrede, M. A., Jordanova, E. S. & Fleuren, G. J. ( 2005; ). Human papillomavirus type 18 variants: histopathology and E6/E7 polymorphisms in three countries. Int J Cancer 114, 422–425.[CrossRef]
    [Google Scholar]
  13. Di Leonardo, A., Linke, S. P., Clarkin, K. & Wahl, G. M. ( 1994; ). DNA damage triggers a prolonged p53-dependent G1 arrest and long-term induction of Cip1 in normal human fibroblasts. Genes Dev 8, 2540–2551.[CrossRef]
    [Google Scholar]
  14. Halpern, A., McBride, A., Myers, G., Baker, C., Wheeler, C. M. & Doorbar, J. (editor) ( 1997; ). Human Papillomaviruses. A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Los Alamos, NM: Los Alamos National Laboratory.
  15. Hecht, J. L., Kadish, A. S., Jiang, G. & Burk, R. D. ( 1995; ). Genetic characterization of the human papillomavirus (HPV) 18 E2 gene in clinical specimens suggests the presence of a subtype with decreased oncogenic potential. Int J Cancer 60, 369–376.[CrossRef]
    [Google Scholar]
  16. Hildesheim, A., Schiffman, M., Bromley, C. & 12 other authors ( 2001; ). Human papillomavirus type 16 variants and risk of cervical cancer. J Natl Cancer Inst 93, 315–318.[CrossRef]
    [Google Scholar]
  17. Im, S. S., Wilczynski, S. P., Burger, R. A. & Monk, B. J. ( 2003; ). Early stage cervical cancers containing human papillomavirus type 18 DNA have more nodal metastasis and deeper stromal invasion. Clin Cancer Res 9, 4145–4150.
    [Google Scholar]
  18. 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.
    [Google Scholar]
  19. Lassus, P., Ferlin, M., Piette, J. & Hibner, U. ( 1996; ). Anti-apoptotic activity of low levels of wild-type p53. EMBO J 15, 4566–4573.
    [Google Scholar]
  20. Lizano, M., Berumen, J., Guido, M. C., Casas, L. & Garcia-Carranca, A. ( 1997; ). Association between human papillomavirus type 18 variants and histopathology of cervical cancer. J Natl Cancer Inst 89, 1227–1231.[CrossRef]
    [Google Scholar]
  21. Mantovani, F. & Banks, L. ( 2001; ). The human papillomavirus E6 protein and its contribution to malignant progression. Oncogene 20, 7874–7887.[CrossRef]
    [Google Scholar]
  22. McLachlin, C. M., Tate, J. E., Zitz, J. C., Sheets, E. E. & Crum, C. P. ( 1994; ). Human papillomavirus type 18 and intraepithelial lesions of the cervix. Am J Pathol 144, 141–147.
    [Google Scholar]
  23. Moscicki, A.-B., Hills, N., Shiboski, S. & 9 other authors ( 2001; ). Risks for incident human papillomavirus infection and low-grade squamous intraepithelial lesion development in young females. JAMA 285, 2995–3002.[CrossRef]
    [Google Scholar]
  24. Myers, G., Bernard, H. U., Delius, H., Favre, J., Icenogle, J., Van Ranst, M. & Wheeler, C. M. (editors) ( 1994; ). Human Papillomaviruses. A Compilation and Analysis of Nucleic Acid and Amino Acid Sequences. Los Alamos, NM: Los Alamos National Laboratory.
  25. Ong, C.-K., Chan, S.-Y., Saveria Campo, M. & 8 other authors ( 1993; ). Evolution of human papillomavirus type 18: an ancient phylogenetic root in Africa and intratype diversity reflect coevolution with human ethnic groups. J Virol 67, 6424–6431.
    [Google Scholar]
  26. Ordóñez, R. M., Espinosa, A. M., Sánchez-González, D. J., Armendáriz-Borunda, J. & Berumen, J. ( 2004; ). Enhanced oncogenicity of Asian-American human papillomavirus 16 is associated with impaired E2 repression of E6/E7 oncogene transcription. J Gen Virol 85, 1433–1444.[CrossRef]
    [Google Scholar]
  27. Pim, D. & Banks, L. ( 1999; ). HPV-18 E6*I protein modulates the E6-directed degradation of p53 by binding to full-length HPV-18 E6. Oncogene 18, 7403–7408.[CrossRef]
    [Google Scholar]
  28. Pim, D., Storey, A., Thomas, M., Massimi, P. & Banks, L. ( 1994; ). Mutational analysis of HPV-18 E6 identifies domains required for p53 degradation in vitro, abolition of p53 transactivation in vivo and immortalisation of primary BMK cells. Oncogene 9, 1869–1876.
    [Google Scholar]
  29. Pim, D., Massimi, P. & Banks, L. ( 1997; ). Alternatively spliced HPV-18 E6* protein inhibits E6 mediated degradation of p53 and suppresses transformed cell growth. Oncogene 15, 257–264.[CrossRef]
    [Google Scholar]
  30. Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J. & Howley, P. M. ( 1990; ). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63, 1129–1136.[CrossRef]
    [Google Scholar]
  31. Schlecht, N. F., Kulaga, S., Robitaille, J. & 8 other authors ( 2001; ). Persistent human papillomavirus infection as a predictor of cervical intraepithelial neoplasia. JAMA 286, 3106–3114.[CrossRef]
    [Google Scholar]
  32. Smith, M. L., Chen, I. T., Zhan, Q., O'Connor, P. M. & Fornace, A. J., Jr ( 1995; ). Involvement of the p53 tumor suppressor in repair of u.v.-type DNA damage. Oncogene 10, 1053–1059.
    [Google Scholar]
  33. Stacey, S. N., Jordan, D., Snijders, P. J. F., Mackett, M., Walboomers, J. M. M. & Arrand, J. R. ( 1995; ). Translation of the human papillomavirus type 16 E7 oncoprotein from bicistronic mRNA is independent of splicing events within the E6 open reading frame. J Virol 69, 7023–7031.
    [Google Scholar]
  34. Stöppler, M. C., Ching, K., Stöppler, H., Clancy, K., Schlegel, R. & Icenogle, J. ( 1996; ). Natural variants of the human papillomavirus type 16 E6 protein differ in their abilities to alter keratinocyte differentiation and to induce p53 degradation. J Virol 70, 6987–6993.
    [Google Scholar]
  35. Walboomers, J. M. M., Jacobs, M. V., Manos, M. M. & 7 other authors ( 1999; ). Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189, 12–19.[CrossRef]
    [Google Scholar]
  36. Werness, B. A., Levine, A. J. & Howley, P. M. ( 1990; ). Association of human papillomavirus type 16 and 18 E6 proteins with p53. Science 248, 76–79.[CrossRef]
    [Google Scholar]
  37. WHO ( 2004; ). The World Helath Report 2004: Changing History, Statistical Annex. Geneva: World Health Organization (http://whqlibdoc.who.int/whr/2004/924156265X.pdf).
  38. Xi, L. F., Koutsky, L. A., Galloway, D. A., Kuypers, J., Hughes, J. P., Wheeler, C. M., Holmes, K. K. & Kiviat, N. B. ( 1997; ). Genomic variation of human papillomavirus type 16 and risk for high grade cervical intraepithelial neoplasia. J Natl Cancer Inst 89, 796–802.[CrossRef]
    [Google Scholar]
  39. Zehbe, I., Wilander, E., Delius, H. & Tommasino, M. ( 1998; ). Human papillomavirus 16 E6 variants are more prevalent in invasive cervical carcinoma than the prototype. Cancer Res 58, 829–833.
    [Google Scholar]
  40. Zhang, H.-G., Wang, J., Yang, X., Hsu, H.-C. & Mountz, J. D. ( 2004; ). Regulation of apoptosis proteins in cancer cells by ubiquitin. Oncogene 23, 2009–2015.[CrossRef]
    [Google Scholar]
  41. zur Hausen, H. ( 2002; ). Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2, 342–350.[CrossRef]
    [Google Scholar]
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