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p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53

Oncogene volume 18, pages 1921–1934 (1999)Cite this article

Abstract

The p53 tumour suppressor is frequently inactivated in human tumours. One form of inactivation results from overexpression of MDM2, that normally forms a negative auto-regulatory loop with p53 and inhibits its activity through complex formation. We have investigated whether disrupting the MDM2-p53 complex in cells that overexpress MDM2 is sufficient to trigger p53 mediated cell death. We find that expression of a peptide homologue of p53 that binds to MDM2 leads to increased p53 levels and transcriptional activity. The consequences are increased expression of the downstream effectors MDM2 and p21WAF1/CIP1, inhibition of colony formation, cell cycle arrest and cell death. There is also a decrease in E2F activity, that might have been due to the known physical and functional interactions of MDM2 with E2F1/DP1. However, this decrease is p53 dependent, as are also colony formation, cell cycle arrest and cell death. These results show that a peptide homologue of p53 is sufficient to induce p53 dependent cell death in cells overexpressing MDM2, and support the notion that disruption of the p53-MDM2 complex is a target for the development of therapeutic agents.

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Acknowledgements

We thank: (1) for the gift of recombinants, cell lines and antibodies, L Andera, A Briones, E Conseiller, N La Thangue, Y Lutz, S Nooner, M Oren, D Shapiro, J Shay, L Tora, N Tsuchida, B Vogelstein and L Zhu; (2) for invaluable help, the IGBMC facilities staff; and (3) for financial assistance, BioAvenir, the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Hópital Universitaire de Strasbourg, the Association pour la Recherche sur le Cancer, the Fondation pour la Recherche Médicale, the Ligue Nationale Française contre le Cancer, the Ligue Régionale (Haut-Rhin) contre le Cancer and the Ligue Régionale (Bas-Rhin) contre le Cancer (the Legs Meyer).

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  1. Roberto Salvi and Manuela Argentini: Roberto Salvi and Manuela Argentini should be considered equal second authors

Authors and Affiliations

  1. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, BP 163, Illkirch, 67404, cedex, France

    Christine Wasylyk, Roberto Salvi, Manuela Argentini & Bohdan Wasylyk

  2. Département d'Oncologie, Centre de Recherche de Vitry-Alfortville, Rhóne-Poulenc Rorer, 13 quai Jules Guesde,, Vitry sur Seine, 94403, Cedex, France

    Christine Dureuil, Isabelle Delumeau & Laurent Debussche

  3. Laboratoire de Biologie Tumorale, 3 rue de la Porte de l'Hópital, Strasbourg, 67085, France

    Joseph Abecassis

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Wasylyk, C., Salvi, R., Argentini, M. et al. p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53. Oncogene 18, 1921–1934 (1999). https://doi.org/10.1038/sj.onc.1202528

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