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Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions

Oncogene volume 18, pages 2201–2211 (1999)Cite this article

Abstract

High risk types of human papillomavirus (HPV) are agents in the aetiology of cervical carcinoma. The products of two early genes, E6 and E7, appear to be the principal transforming proteins. Studies of various monolayer cell culture systems have shown that the E7 oncoprotein of human papillomavirus type 16 is able to neutralize or bypass the inhibitory effect of the cell cycle-dependent kinase (CDK) inhibitors (CKIs) p21WAF1/CIP1 and p27KIP1. To understand whether the p21WAF1/CIP1 or p27KIP1 neutralization also plays a role in vivo, we performed studies on clinical specimens. Forty-five cervical biopsies, including HPV-negative mucosa, HPV 16-positive preinvasive (low and high grade lesions) and invasive neoplasia as well as HPV 6-positive condyloma acuminatum were analysed by single and double immunohistology. We examined the positive cell cycle regulator cyclin A and the universal cell cycle marker Ki67 as well as the negative cell cycle regulators p21WAF1/CIP1 and p27KIP1. Here, we show that in a significant fraction of cells the G1 block can be overcome despite high levels of CKIs in HPV lesions. This phenomenon, which was more evident for p21WAF1/CIP1 than for p27KIP1 was most marked in low grade lesions and in condylomata acuminata, in which a high viral productivity is expected. These results indicate that the overriding of CKI inactivation by viral oncoproteins appears to be a conserved property between low and high risk HPV types. We conclude that the CKI neutralization by HPVs is likely to be required for viral DNA replication rather than for malignant transformation of the host cell.

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Acknowledgements

We are grateful to Professor H zur Hausen for his continuous interest in our work and for kindest support. We thank Professors P Bannasch and D Komitowski for a friendly atmosphere while using their laboratory facilities, and Mrs I Schuster for cutting the sections. We further thank Dr J Pines for the cyclin A antibody, Dr L Ringrose for language review, Dr W Rittgen for the statistical analysis, Professor L Gissmann and Dr P Jansen-Dürr for stimulating discussions. This work was supported by a postdoctoral fellowship of the Swedish Medical Society (Svenska Lákaresállskapet), Stockholm, Sweden to Ingebord Zehbe, and by postdoctoral fellowship of Von Humboldt Stiftung to Marianna Alunni-Fabbroni.

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Authors and Affiliations

  1. Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Heidelberg, D-69120, Germany

    Ingeborg Zehbe, Marianna Alunni-Fabbroni, Evi Bakos & Massimo Tommasino

  2. Organisation komplexer Genome, Deutsches Krebsforschungszentrum, Heidelberg, D-69120, Germany

    Andreas Rätsch

  3. Biomedizinische Strukturforschung, Deutsches Krebsforschungszentrum, Heidelberg, D-69120, Germany

    Annett Burzlaff

  4. Gynäkologische Molekularbiologie, Klinik für Frauenheilkunde & Geburtshilfe, Jena, D-07740, Germany

    Matthias Dürst

  5. Department of Genetics and Pathology, University of Uppsala, Uppsala, S-75185, Sweden

    Erik Wilander

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Zehbe, I., Rätsch, A., Alunni-Fabbroni, M. et al. Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions. Oncogene 18, 2201–2211 (1999). https://doi.org/10.1038/sj.onc.1202549

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