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Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts

Oncogene volume 19, pages 2277–2285 (2000)Cite this article

Abstract

The HPV16 E7 oncoprotein neutralizes several cell cycle checkpoints, favouring the entry of quiescent cells into S phase. This activity is mediated in part by association of E7 with the pocket proteins and consequent activation of E2F transcription factors. In addition, HPV16 E7 protein is able to promote apoptosis. In this study we demonstrate that the ability to induce apoptosis is a common property of E7s belonging to both benign and malignant HPV types. The E7-induced apoptosis is mediated by inactivation of pRb, whilst neutralization of the other two pRB-related proteins, p107 and 130, is not sufficient to trigger apoptosis. Moreover, we show that certain point mutations in the conserved region 1 (CR1) of HPV16 E7 abolish the induction of apoptosis without altering the ability to stimulate S phase. Thus, these two E7-mediated cellular events, apoptosis and S phase entry, can be separated in immortalized rodent fibroblasts. Our findings demonstrate that the E7-mediated pRb destabilization is not required for its ability to drive quiescent cells into S phase and to induce apoptosis. Finally, expression of E7 proteins in NIH3T3, which lack a functional p19ARF, does not lead to p53 accumulation, indicating that the E7 impacts upon additional cellular pathways to promote apoptosis.

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Acknowledgements

We are grateful to Professor Harald zur Hausen for his continuous support and interest in our work. We would also like to thank Professor Jean Rommelaere and Dr Melanie Ott for critical reading of the manuscript. M Alunni-Fabbroni was supported by a postdoctoral fellowship program of Alexander von Humboldt-Stiftung and S Caldeira was supported by a PRAXIS XXI doctoral fellowship (Sub Programa Ciencia e Tecnologia do 2° Quadro Comunitario de Apoio).

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  1. Marianna Alunni-Fabbroni & Laurent Deleu

    Present address: Center for Cancer Biology, University of Rochester Medical Center, 601 Elmwood Ave., Rochester, 14642, NY, USA

Authors and Affiliations

  1. Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, INF 242, Heidelberg, D-69120, Germany

    Marianna Alunni-Fabbroni, Laurent Deleu, Sandra Caldeira, Marianna Giarrè, Mariangela Dell' Orco & Massimo Tommasino

  2. Imperial Cancer Research Fund, 44 Lincoln's Inn Fields, London, UK

    Trevor Littlewood

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Alunni-Fabbroni, M., Littlewood, T., Deleu, L. et al. Induction of S phase and apoptosis by the human papillomavirus type 16 E7 protein are separable events in immortalized rodent fibroblasts. Oncogene 19, 2277–2285 (2000). https://doi.org/10.1038/sj.onc.1203570

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