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p53 mRNA controls p53 activity by managing Mdm2 functions

Nature Cell Biology volume 10, pages 1098–1105 (2008)Cite this article

Abstract

The E3 ubiquitin ligase Mdm2 is a focal regulator of p53 tumour suppressor activity. It binds p53, promoting its polyubiquitination and degradation, and also controls p53 synthesis. However, it is not known how this dual function of Mdm2 on p53 synthesis and degradation is achieved. Here we show that the p53 mRNA region encoding the Mdm2-binding site interacts directly with the RING domain of Mdm2. This impairs the E3 ligase activity of Mdm2 and promotes p53 mRNA translation. We also show that introduction of cancer-derived single silent point-mutations in the p53 mRNA weakens its binding to Mdm2 and results in reduced p53 activity. These data are consistent with a mechanism by which changes in silent nucleotides can affect the function of the encoded protein, and indicate that Mdm2-mediated control of p53 synthesis and degradation has evolved in the p53 mRNA sequence and its encoded amino acids.

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Figure 1: Mdm2-dependent control of p53 mRNA translation is mediated by the p53 mRNA sequence (MBD-ES) that encodes the Mdm2-binding domain (MBD).
Figure 2: Mdm2 interacts directly and specifically with the MBD-ES of p53 mRNA to induce p53 translation.
Figure 3: p53 mRNA controls Mdm2 E3 ubiquitin ligase activity.
Figure 4: The Mdm2–p53 mRNA interaction controls p53 activity.

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Acknowledgements

This work was supported by AICR, AVENIR/INSERM and La Ligue Contre le Cancer. M.M.C. was supported by grant SFRH/BD/16697/2004 from the Fundação para a Ciência e a Tecnologia of Portugal. Bacterial purified hMdm2 was a gift from D. Xirodimas and we are thankful to Chris M. Brown and Nattanan Panjaworayan, Dunedin, New Zealand for providing the TriFC constructs. Anti-p53 and anti-Mdm2 antibodies were a gift from B. Vojtesek. Flow cytometry and immunofluorescence microscopy experiments were performed at the Imagery Department of the Institut Universitaire d'Hematologie-IFR105.

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  1. Inserm U716, Pharmacologie Expérimentale, Institut Génétique Moléculaire, Hôpital St Louis and Université Paris 7, 27 rue Juliette Dodu, Paris, 75010, France

    Marco M. Candeias, Laurence Malbert-Colas, Darren J. Powell, Chrysoula Daskalogianni, Magda M. Maslon, Nadia Naski, Karima Bourougaa, Fabien Calvo & Robin Fåhraeus

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Contributions

R.F. and M.M.C. designed the project; M.M.C., L.M.-C. and M.M.M. performed the experiments; all authors contributed to data analysis; R.F., M.M.C. and C.D. wrote the manuscript.

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Correspondence to Robin Fåhraeus.

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Supplementary Figures S1, S2, S3, S4 and S5 (PDF 875 kb)

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Candeias, M., Malbert-Colas, L., Powell, D. et al. p53 mRNA controls p53 activity by managing Mdm2 functions. Nat Cell Biol 10, 1098–1105 (2008). https://doi.org/10.1038/ncb1770

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