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Extinction of Rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway

Oncogene volume 19, pages 2377–2385 (2000)Cite this article

Abstract

Apoptosis is a normal physiological process which eliminates cells that do not receive adequate extracellular signals. One of the pathways signalling apoptosis is controlled by the small GTPases of the Rho family, also involved in cell proliferation, differentiation and motility. Another major apoptosis signalling pathway involves the p53 tumour suppressor which is activated by a variety of stress and mediates growth arrest or apoptosis in normal cells. We show here that upon detachment from the extracellular matrix, fibroblasts undergo rapid apoptosis that can be rescued by constitutive activation of Rac1 and Cdc42Hs GTPases. Conversely, inhibition of Rac1 and Cdc42Hs efficiently triggers apoptosis in adherent cells. Interestingly, apoptosis is not observed in p53−/− cells either cultured in suspension or inhibited for Rac1 and Cdc42Hs activity. Moreover, Rac1 and Cdc42Hs extinction in normal cells activates endogenous p53. Using specific inhibitors of MAPK pathways, we demonstrate that, in our experimental system, p38 signals survival, while ERK activity is required for apoptosis. Our data constitute the first demonstration that Rac1 and Cdc42Hs control pathways that require simultaneous signalling through MAPK ERK and p53 to induce apoptosis.

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Acknowledgements

We are grateful to Drs JM Blanchard, A Brunet, P Chavrier, A Hall, C Norbury and J Piette for different plasmids and reagents used in this work. We thank Dr Danièle Mathieu for support and discussions and Dr Naomi Taylor for critical comments on the manuscript. Supported by Association pour la Recherche contre le Cancer, Ligue Nationale contre le Cancer, INSERM and CNRS. P Lassus was a recipient of a fellowship from Ligue Nationale contre le Cancer.

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Author notes

  1. Patrice Lassus

    Present address: Cold Spring Harbor Laboratory, P.O. Box 100, 1 Bungtown Road, Cold Spring Harbor, 11724, NY, USA

  2. Patrice Lassus and Pierre Roux: P Lassus and P Roux contributed equally to this work

Authors and Affiliations

  1. Institut de Génétique Moléculaire, CNRS UMR5535, IFR 24, 1919 Route de Mende, Montpellier, cedex 5, F-34293, France

    Patrice Lassus, Olivier Zugasti, Alexandre Philips & Urszula Hibner

  2. Centre de Recherche en Biochimie Macromoléculaire, CNRS UPR1086, IFR 24, 1919 route de Mende, Montpellier, cedex 5, F-34293, France

    Pierre Roux & Philippe Fort

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Lassus, P., Roux, P., Zugasti, O. et al. Extinction of Rac1 and Cdc42Hs signalling defines a novel p53-dependent apoptotic pathway. Oncogene 19, 2377–2385 (2000). https://doi.org/10.1038/sj.onc.1203553

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