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Accelerated MDM2 auto-degradation induced by DNA-damage kinases is required for p53 activation

Jayne M Stommel1, Geoffrey M Wahl

  • 1Department of Biology, University of California, San Diego, CA, USA.

The EMBO Journal
|March 19, 2004
PubMed

Insights

The E3 ubiquitin ligase MDM2 targets p53 for degradation. DNA damage destabilizes MDM2, allowing p53 activation, revealing a new regulatory step in the p53 pathway.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • The p53 protein is a tumor suppressor that halts the proliferation of genetically unstable cells.
  • The E3 ubiquitin ligase MDM2 antagonizes p53, promoting the viability of unstressed cells.
  • MDM2 induces p53 degradation in both nuclear and cytoplasmic compartments.

Purpose of the Study:

  • To investigate the mechanisms of p53 activation during DNA damage response despite high MDM2 levels.
  • To elucidate the role of MDM2 stability in regulating p53 activity post-DNA damage.

Main Methods:

  • Demonstration of MDM2-induced p53 degradation in nucleus and cytoplasm.
  • Investigation of p53 and MDM2 dynamics in stressed cells.
  • Analysis of MDM2 destabilization mechanisms involving damage-activated kinases and auto-ubiquitination.
  • Assessment of p53 stability and transcriptional activity correlated with MDM2 stability.
  • Experimental blocking of MDM2 destabilization in DNA-damaged cells.

Main Results:

  • DNA damage was shown to destabilize MDM2 through a process involving activated kinases and auto-ubiquitination.
  • p53 remained stable and transcriptionally active when MDM2 was unstable.
  • p53 became unstable and inactive as the DNA damage response subsided and MDM2 stabilized.
  • Inhibition of MDM2 destabilization in DNA-damaged cells abrogated p53 target gene activation.

Conclusions:

  • Controlled degradation of MDM2 is a critical regulatory mechanism for p53.
  • This finding introduces a new step in the regulation of the p53 pathway, crucial for cellular response to DNA damage.

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