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  • Original Paper
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Anti-apoptotic activity of p53 maps to the COOH-terminal domain and is retained in a highly oncogenic natural mutant

Oncogene volume 18, pages 4699–4709 (1999)Cite this article

Abstract

The tumour suppressor p53 plays a complex role in the regulation of apoptosis. High levels of wild type p53 potentiate the apoptotic response, while physiological range, low levels of the protein have an anti-apoptotic activity in serum starved immortalized fibroblasts. Here we report that primary fibroblast-like cells that show normal growth control are also efficiently protected from apoptosis by the endogenous p53 activity. The capacity to inhibit apoptosis is not restricted to the wild type protein: the R→H175 p53 mutant fully retains the anti-apoptotic activity of the wild type p53, providing a possible explanation for its high oncogenicity. Using a series of point and deletion mutants of p53 under the control of tetracycline-regulated promoter we show that certain mutants, like the wild type, protect cells at low levels but lead to apoptosis when overexpressed. This latter effect is lost upon deletion of a proline-rich domain in the NH2 part of the protein. The anti-apoptotic activity can be mapped to the extreme carboxy-terminal part of the protein and is therefore independent of other well characterized p53 activities. Our results add a new level of complexity to the network of interactions mediated by p53 in normal physiology and pathology.

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Acknowledgements

We are very grateful to Drs John Jenkins, Moshe Oren and Laurent Debussche for providing plasmids with mutant p53, Dr Nicole Basset-Seguin for the E6, Dr Chris Norbury for the CD2 expression vectors, Dr Alain Sarasin for the AS 198 cells and Dr Jean Marie Blanchard for the anti-GAPDH antibody. We thank Dr Bob Hipskind for comments on the manuscript. Supported by Association pour la Recherche contre le Cancer, Ligue Nationale contre le Cancer, INSERM and CNRS. P Lassus is a recipient of a fellowship from ARC.

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  1. Christelle Bertrand

    Present address: Laboratoire de Différenciation et Croissance, INRA, 2, place Viala, 34060, Montpellier, Cedex 1

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  1. Institut de Génétique Moléculaire, CNRS UMR 5535, 1919 route de Mende, 34293, Montpellier, Cedex 5, France

    Patrice Lassus, Christelle Bertrand, Olivier Zugasti, Jean-Philippe Chambon, Danièle Mathieu-Mahul & Urszula Hibner

  2. CNRS UMR 218, Institut Curie, 26 rue d'Ulm, 75248, Paris, Cedex 5, France

    Thierry Soussi

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Lassus, P., Bertrand, C., Zugasti, O. et al. Anti-apoptotic activity of p53 maps to the COOH-terminal domain and is retained in a highly oncogenic natural mutant. Oncogene 18, 4699–4709 (1999). https://doi.org/10.1038/sj.onc.1202841

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