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The p53 mRNA-Mdm2 interaction

Nadia Naski1, Madhavsai Gajjar, Karima Bourougaa

  • 1INSERM Unité 716, Laboratoire de Pharmacologie, Institut de Génétique Moléculaire, Université Paris 7, 27 rue Juliette Dodu, Paris, France.

Cell Cycle (Georgetown, Tex.)
|December 25, 2008
PubMed

Insights

The E3 ligase Mdm2 regulates p53 activity through complex feedback. Mdm2 stimulates p53 mRNA translation and protein degradation, with overlapping domains suggesting co-evolution of these functions.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • The E3 ligase Mdm2 is a critical regulator of the tumor suppressor p53.
  • Regulation involves transcription, mRNA translation, and protein degradation.
  • Mdm2's role as a positive regulator of p53 activity is an emerging area of research.

Purpose of the Study:

  • To investigate how p53-Mdm2 protein-protein and mRNA-Mdm2 interactions influence Mdm2-mediated control of p53 expression.
  • To utilize the Phe19Ala p53 mutant to elucidate these regulatory mechanisms.
  • To explore the evolutionary origins and functional significance of the p53-Mdm2 feedback system.

Main Methods:

  • Analysis of p53-Mdm2 protein-protein interactions.
  • Investigation of p53 mRNA-Mdm2 interactions, including binding sites and functional consequences.
  • Utilizing the Phe19Ala p53 mutant to dissect specific regulatory roles.
  • Comparative analysis of Mdm2's RNA binding and E3 ligase domains.

Main Results:

  • Mdm2 binding to p53 mRNA stimulates p53 translation.
  • This interaction concurrently suppresses Mdm2's ability to promote p53 polyubiquitination and degradation.
  • The p53 mRNA sequence interacting with Mdm2's N-terminus is identical to the sequence interacting with the Mdm2 RING domain.
  • Overlapping RNA binding and E3 ligase domains in Mdm2 suggest co-evolution of p53 synthesis and degradation control.

Conclusions:

  • The p53-Mdm2 interaction is a sophisticated feedback system regulating p53 expression at multiple levels.
  • Insights into this regulation can illuminate the system's origin and the function of Mdm2 isoforms.
  • The dual function of Mdm2 in controlling p53 synthesis and degradation highlights a conserved regulatory strategy.

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