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The contribution of the RING finger domain of MDM2 to cell cycle progression

Oncogene volume 19, pages 3849–3857 (2000)Cite this article

Abstract

The MDM2 oncoprotein binds to p53 and abrogates p53-mediated G1 arrest and apoptosis. We show that MDM2 over-expression accelerates cell cycle progression of RPMI2650 cells by overcoming the negative effect of endogenous wild type p53 at the G1/S checkpoint. The interaction with p53 and transcription inhibition are necessary but not sufficient. The RING finger domain of MDM2 is also required for the positive effect of MDM2 on the cell cycle. Surprisingly, several point mutants in the zinc binding sites of the RING finger are fully competent for cell cycle stimulation even though they abolish MDM2-directed degradation of p53 and MDM2 E3-ligase activity. In contrast, alterations in and around the cryptic nucleolar localization sequence (KR motif) inhibit MDM2-mediated cell cycle progression as well as p53 degradation and MDM2 E3 ligase activity. We found that all the RING mutants decrease inhibition of both p53 dependent reporters and endogenous p21CIP1/WAF1/SDI1. These results indicate that the RING finger of MDM2 has a role in the regulation of the cell cycle that is independent of p53 degradation and endogenous p21CIP1/WAF1/SDI1 regulation.

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Acknowledgements

M Argentini and N Barboule contributed equally to this work. We thank: (1) for analysing the p53 status of RPMI2650, D Muller and J Abecassis; (2) for critical reading of the manuscript, P Anglard; (3) for the gift of recombinants and antibodies, D Bohman, N La Thangue, T Lèveillard, A Levine, Y Lutz, M Oren, J Shay, MB Vogelstein and L Zhu; (3) for invaluable help, the IGBMC facilities staff; (4) for fellowships for M Argentini, the Ligue Régional (Bas-Rhin) contre le Cancer, the Association pour la Recherche sur le Cancer and Ministère de la Recherche et de Technologie (4) for a fellowship for N Barboule, Rhone-Poulenc; and (5) for financial assistance, BioAvenir (Rhone-Poulenc), the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Hôpital 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.

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  1. Manuela Argentini and Nadia Barboule: The first two authors contributed equally to this work

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

    Manuela Argentini, Nadia Barboule & Bohdan Wasylyk

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Argentini, M., Barboule, N. & Wasylyk, B. The contribution of the RING finger domain of MDM2 to cell cycle progression. Oncogene 19, 3849–3857 (2000). https://doi.org/10.1038/sj.onc.1203737

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