The human papillomavirus type 16 (HPV-16) status of 43 cervical biopsies, which had been characterized histologically as normal, various grades of cervical intraepithelial neoplasia (CIN) and invasive squamous cell carcinoma, was examined by using (i) a novel antibody against the HPV-16 E2 protein, (ii) sensitive HPV-16 DNA hybridization and (iii) microdissection/PCR for the E2 ORF. The data indicate that E2 protein expression is highest in koilocytes in lower-grade CIN (I), but decreases with increasing grade, whereas the detection of HPV DNA is delayed until CIN I/II, rising to the highest levels in carcinoma cells. Co-localization of E2 with HPV-16 DNA-positive cells was most commonly observed in koilocytes in CIN II lesions. PCR analyses of microdissected epithelium from the same or serial sections indicated that E2 ORFs were retained in an intact form in a number of higher-grade CIN lesions and invasive carcinomas.


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  1. Bouvard, V., Storey, A., Pim, D. & Banks, L. (1994). Characterization of the human papillomavirus E2 protein: evidence of trans-activation and trans-repression in cervical keratinocytes.EMBO Journal 13, 5451-5459. [Google Scholar]
  2. Chiang, C.-M., Ustav, M., 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.[CrossRef] [Google Scholar]
  3. Chow, L. T. & Broker, T. R. (1994). Papillomavirus DNA replication.Intervirology 37, 150-158. [Google Scholar]
  4. Del Vecchio, A. M., Romanczuk, H., Howley, P. M. & Baker, C. C. (1992). Transient replication of human papillomavirus DNAs.Journal of Virology 66, 5949-5958. [Google Scholar]
  5. Desaintes, C., Goyat, S., Garbay, S., Yaniv, M. & Thierry, F. (1999). Papillomavirus E2 induces p53-independent apoptosis in HeLa cells.Oncogene 18, 4538-4545.[CrossRef] [Google Scholar]
  6. DiSaia, P. J. & Creasman, W. T. (1989). Preinvasive disease of the cervix, vagina and vulva. In Clinical Gynecologic Oncology, 3rd edn, pp. 58–125. St Louis, MO: C. V. Mosby.
  7. Fowler, J. (1993). Screening for cervical cancer. Current terminology, classification, and technique.Postgraduate Medicine 93, 57-70. [Google Scholar]
  8. Graham, D. A. & Herrington, C. S. (1998). The induction of chromosome abnormalities by human papillomaviruses.Papillomavirus Report 9, 1-5. [Google Scholar]
  9. Ham, J., Dostatni, N., Gauthier, J.-M. & Yaniv, M. (1991). The papillomavirus E2 protein: a factor with many talents.Trends in Biochemical Sciences 16, 440-444.[CrossRef] [Google Scholar]
  10. Higgins, G. D., Uzelin, D. M., Phillips, G. E. & Burrell, C. J. (1991). Presence and distribution of human papillomavirus sense and antisense RNA transcripts in genital cancers.Journal of General Virology 72, 885-895.[CrossRef] [Google Scholar]
  11. Kalantari, M., Karlsen, F., Kristensen, G., Holm, R., Hagmar, B. & Johansson, B. (1998). Disruption of the E1 and E2 reading frames of HPV 16 in cervical carcinoma is associated with poor prognosis.International Journal of Gynecological Pathology 17, 146-153.[CrossRef] [Google Scholar]
  12. Krajinovic, M., Lazic, J., Stanimirovic, B., Diklic, V. & Savic, A. (1993). The E2 region of HPV 16 in relation to different types of cervical lesions.Journal of Medical Virology 41, 1-5. [Google Scholar]
  13. Lusky, M., Hurwitz, J. & Seo, Y.-S. (1994). The bovine papillomavirus E2 protein modulates the assembly of but is not stably maintained in a replication-competent multimeric E1-replication origin complex.Proceedings of the National Academy of Sciences, USA 91, 8895-8899.[CrossRef] [Google Scholar]
  14. Macintosh, C. A., Stower, M., Reid, N. & Maitland, N. J. (1998). Precise microdissection of human prostate cancers reveals genotypic heterogeneity.Cancer Research 58, 23-28. [Google Scholar]
  15. Maitland, N. J., Conway, S., Wilkinson, N. S., Ramsdale, J., Morris, J. R., Sanders, C. M., Burns, J. E., Stern, P. L. & Wells, M. (1998). Expression patterns of the human papillomavirus type 16 transcription factor E2 in low- and high-grade cervical intraepithelial neoplasia.Journal of Pathology 186, 275-280.[CrossRef] [Google Scholar]
  16. 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.[CrossRef] [Google Scholar]
  17. Resnick, M., Lester, S., Tate, J. E., Sheets, E. E., Sparks, C. & Crum, C. P. (1996). Viral and histopathologic correlates of MN and MIB-1 expression in cervical intraepithelial neoplasia.Human Pathology 27, 234-239.[CrossRef] [Google Scholar]
  18. Richart, R. M., Masood, S., Syrjänen, K. J., Vassilakos, P., Kaufman, R. H., Meisels, A., Olszewski, W. T., Sakamoto, A., Stoler, M. H., Vooijs, G. P. & Wilbur, D. C.(1998). Human papillomavirus. International Academy of Cytology – IAC Task Force summary. Diagnostic cytology towards the 21st century: an international expert conference and tutorial.Acta Cytologica 42, 50-58.[CrossRef] [Google Scholar]
  19. Rocha-Zavaleta, L., Jordan, D., Pepper, S., Corbitt, G., Clarke, F., Maitland, N. J., Sanders, C. M., Arrand, J. R., Stern, P. L. & Stacey, S. N. (1997). Differences in serological IgA responses to recombinant baculovirus-derived human papillomavirus E2 protein in the natural history of cervical neoplasia.British Journal of Cancer 75, 1144-1150.[CrossRef] [Google Scholar]
  20. Sanders, C. M., Stern, P. L. & Maitland, N. J. (1995). Characterization of human papillomavirus type 16 E2 protein and subdomains expressed in insect cells.Virology 211, 418-433.[CrossRef] [Google Scholar]
  21. Schneider, A., Oltersdorf, T., Schneider, V. & Gissmann, L. (1987). Distribution pattern of human papilloma virus 16 genome in cervical neoplasia by molecular in situ hybridization of tissue sections.International Journal of Cancer 39, 717-721.[CrossRef] [Google Scholar]
  22. 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.[CrossRef] [Google Scholar]
  23. Sedman, J. & Stenlund, A. (1996). The initiator protein E1 binds to the bovine papillomavirus origin of replication as a trimeric ring-like structure.EMBO Journal 15, 5085-5092. [Google Scholar]
  24. Singer, M. & Berg, P. (1991). SV40 early gene transcription. In Genes & Genomes, pp. 489-504. Edited by C. Dempster & S. S. Wright. Mill Valley, CA: University Science Books.
  25. Stubenrauch, F., Colbert, A. M. E. & Laimins, L. A. (1998). Transactivation by the E2 protein of oncogenic human papillomavirus type 31 is not essential for early and late viral functions.Journal of Virology 72, 8115-8123. [Google Scholar]
  26. Webster, K., Parish, J., Pandya, M., Stern, P. L., Clarke, A. R. & Gaston, K. (2000). The human papillomavirus (HPV) 16 E2 protein induces apoptosis in the absence of other HPV proteins and via a p53-dependent pathway.Journal of Biological Chemistry 275, 87-94.[CrossRef] [Google Scholar]
  27. Yee, C., Krishnan-Hewlett, I., Baker, C. C., Schlegel, R. & Howley, P. M. (1985). Presence and expression of human papillomavirus sequences in human cervical carcinoma cell lines.American Journal of Pathology 119, 361-366. [Google Scholar]
  28. Ziol, M., Di Tomaso, C., Biaggi, A., Tepper, M., Piquet, P., Carbillon, L., Uzan, M. & Guettier, C. (1998). Virological and biological characteristics of cervical intraepithelial neoplasia grade I with marked koilocytotic atypia.Human Pathology 29, 1068-1073.[CrossRef] [Google Scholar]
  29. zur Hausen, H. (1994). Molecular pathogenesis of cancer of the cervix and its causation by specific human papillomavirus types.Current Topics in Microbiology and Immunology 186, 131-156. [Google Scholar]

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