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MDM2 overexpression generates a skin phenotype in both wild type and p53 null mice

Oncogene volume 18, pages 1419–1434 (1999)Cite this article

Abstract

The MDM2 proto-oncogene is overexpressed in human tumours and regulates the activities of the tumour suppressors p53 and pRB. We created mice that overexpress MDM2 under the control of the CMV promoter. These mice did not display an increased tumour incidence, but rather a specific skin phenotype, characterized by desquamation and hyperkeratosis. Transgenic MDM2 was found to be overexpressed in the epidermis, a tissue that normally expresses high levels of MDM2. The phenotype appeared during the first week after birth and then lessened with age, closely following the level of expression of the transgene. MDM2 overexpression was associated with an increase in proliferation in the basal layer, thickening of the epidermis, altered expression of the differentiation markers cytokeratin CK14, CK10 and CK1, and a decrease in the size and the number of granules that contain products of differentiation. Transgenic mice on a p53 null background displayed similar although not identical changes, showing that the effects of MDM2 are to a certain degree p53 independent. The skin is a major site of MDM2 expression in mice, raising the possibility that MDM2 overexpression perturbs the normal pattern of MDM2 expression and inhibits differentiation of the epidermis.

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Acknowledgements

We thank T Leveillard and S Yuspa for antibodies, S Sengupta for critical reading of the manuscript, members of the Gene Medecine Department of Rhone-Poulenc (especially Bruno Tocque, Laurent Bracco, Laurent Debussche and Emmanuel Conseiller) for continual help and encouragement, the staff of the IGBMC facilities for their invaluable help, the Bioavenir Program for a fellowship for Moussa Alkhalaf, the Ligue contre le Cancer for a fellowship for Gitali Ganguli, and various funding agencies including: the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Hospitalier 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, the Ligue Régionale (Bas-Rhin) contre le Cancer (the Legs Meyer) and the Bioavenir Program (Ministère de la Recherche et Ministère de l'Industrie).

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  1. M Alkhalaf and G Ganguli: M Alkhalaf and G Ganguli contributed equally to this manuscript

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

    M Alkhalaf, G Ganguli, N Messaddeq, M Le Meur & B Wasylyk

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Alkhalaf, M., Ganguli, G., Messaddeq, N. et al. MDM2 overexpression generates a skin phenotype in both wild type and p53 null mice. Oncogene 18, 1419–1434 (1999). https://doi.org/10.1038/sj.onc.1202448

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