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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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Purification of Ubiquitinated p53 Proteins from Mammalian Cells

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The p53 mRNA-Mdm2 interaction controls Mdm2 nuclear trafficking and is required for p53 activation following DNA

Madhavsai Gajjar1, Marco M Candeias, Laurence Malbert-Colas

  • 1Cibles Therapeutiques, INSERM Unité, Institut de Génétique Moléculaire, Université Paris, IUH Hôpital St. Louis, Paris, France.

Cancer Cell
|January 24, 2012
PubMed

Insights

The ATM kinase regulates the tumor suppressor p53 by controlling Mdm2. ATM-dependent Mdm2 phosphorylation switches Mdm2 to promote p53 synthesis via mRNA binding, stabilizing p53 after DNA damage.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • ATM kinase and p53 are crucial tumor suppressors regulating the genotoxic stress response.
  • Mdm2, an ATM substrate, modulates p53 activity through degradation or mRNA binding.
  • The dual role of Mdm2 in p53 regulation remains unclear.

Purpose of the Study:

  • To elucidate the regulation and physiological role of Mdm2's dual function toward p53.
  • To investigate how ATM activity influences Mdm2's interaction with p53 mRNA.

Main Methods:

  • Investigated ATM-dependent phosphorylation of Mdm2 at Ser395.
  • Assessed Mdm2's interaction with p53 mRNA.
  • Examined SUMO-conjugation and nucleoli localization of Mdm2.
  • Studied the impact of inhibiting the p53 mRNA-Mdm2 interaction on p53 stabilization.

Main Results:

  • ATM-dependent phosphorylation of Mdm2 at Ser395 is essential for p53 mRNA binding.
  • This phosphorylation event promotes Mdm2 SUMO-conjugation and nucleoli accumulation.
  • Disruption of the p53 mRNA-Mdm2 interaction inhibits p53 stabilization and activation post-DNA damage.

Conclusions:

  • ATM kinase activity switches Mdm2's function from a negative to a positive regulator of p53.
  • This switch is mediated by Mdm2's interaction with p53 mRNA, influenced by ATM phosphorylation.
  • The findings reveal a novel mechanism controlling p53 activity in response to DNA damage.

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