Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms

Robert Stad; Natalie A. Little; Dimitris P. Xirodimas; Ruth Frenk; Alex J. van der Eb; David P. Lane; Mark K. Saville; Aart G. Jochemsen

doi:10.1093/embo-reports/kve227

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Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms

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Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms

Robert Stad, Natalie A. Little, Dimitris P. Xirodimas, Ruth Frenk, Alex J. van der Eb, David P. Lane, Mark K. Saville et Aart G. Jochemsen

EMBO reports, Vol.2(11), pp.1029-1034

11/2001

DOI: https://doi.org/10.1093/embo-reports/kve227

PMID: 11606419

Résumé

Scientific Reports

The p53 protein maintains genomic integrity through its ability to induce cell cycle arrest or apoptosis in response to various forms of stress. Substantial regulation of p53 activity occurs at the level of protein stability, largely determined by the activity of the Mdm2 protein. Mdm2 targets both p53 and itself for ubiquitylation and subsequent proteasomal degradation by acting as an ubiquitin ligase, a function that needs an intact Mdm2 RING finger. For efficient degradation of p53 nuclear export appears to be required. The Mdmx protein, structurally homologous to Mdm2, does not target p53 for degradation, but even stabilizes both p53 and Mdm2, an activity most likely mediated by heterodimerization of the RING fingers of Mdm2 and Mdmx. Here we show that Mdmx expression leads to accumulation of ubiquitylated, nuclear p53 but does not significantly affect the Mdm2-mediated ubiquitylation of p53. In contrast, Mdmx stabilizes Mdm2 by inhibiting its self-ubiquitylation.

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Titre: Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms
Créateurs - sans rôle: Robert Stad - Leiden University Medical Centre, Department of Molecular and Cell Biology and Centre for Biomedical Genetics, PO Box 9503, 2300 RA Leiden, The Netherlands and University of Dundee, Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Natalie A. Little - Leiden University Medical Centre, Department of Molecular and Cell Biology and Centre for Biomedical Genetics, PO Box 9503, 2300 RA Leiden, The Netherlands and University of Dundee, Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Dimitris P. Xirodimas - Leiden University Medical Centre, Department of Molecular and Cell Biology and Centre for Biomedical Genetics, PO Box 9503, 2300 RA Leiden, The Netherlands and University of Dundee, Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Ruth Frenk - Leiden University Medical Centre, Department of Molecular and Cell Biology and Centre for Biomedical Genetics, PO Box 9503, 2300 RA Leiden, The Netherlands and University of Dundee, Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Alex J. van der Eb - Leiden University Medical Centre, Department of Molecular and Cell Biology and Centre for Biomedical Genetics, PO Box 9503, 2300 RA Leiden, The Netherlands and University of Dundee, Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
David P. Lane - Leiden University Medical Centre, Department of Molecular and Cell Biology and Centre for Biomedical Genetics, PO Box 9503, 2300 RA Leiden, The Netherlands and University of Dundee, Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Mark K. Saville - Leiden University Medical Centre, Department of Molecular and Cell Biology and Centre for Biomedical Genetics, PO Box 9503, 2300 RA Leiden, The Netherlands and University of Dundee, Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Aart G. Jochemsen - Leiden University Medical Centre, Department of Molecular and Cell Biology and Centre for Biomedical Genetics, PO Box 9503, 2300 RA Leiden, The Netherlands and University of Dundee, Department of Surgery and Molecular Oncology, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
Détails de publication: EMBO reports, Vol.2(11), pp.1029-1034
Éditeur: Oxford University Press
Nombre de pages: 6
Identifiants: 99149611809311
Unité académique: Centre de Recherche en Biologie Cellulaire de Montpellier - CRBM
Langue: English
Type de ressource: Journal article