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DNA damage-induced phosphorylation of MdmX at serine 367 activates p53 by targeting MdmX for Mdm2-dependent

Koji Okamoto1, Kenji Kashima, Yaron Pereg

  • 1Radiobiology Division, National Cancer Center Research Institute, Tsukiji 5-1-1, Chuo-ku, Tokyo 104-0045, Japan. kojokamo@gan2.res.ncc.go.jp

Molecular and Cellular Biology
|October 18, 2005
PubMed

Insights

Mdmx phosphorylation at serine 367 (S367) is key for p53 activation after DNA damage. This modification promotes Mdmx degradation, enhancing cellular defense against cancer.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Signaling

Background:

  • p53 activity regulation is vital for cancer prevention.
  • Mdmx and Mdm2 maintain low p53 levels in unstressed cells.
  • Biochemical mechanisms of Mdmx regulation of p53 are unclear.

Purpose of the Study:

  • To elucidate the biochemical mechanisms of Mdmx regulation of p53 activity.
  • To identify Mdmx-binding proteins and their role in p53 regulation.
  • To investigate the role of serine 367 (S367) phosphorylation in Mdmx function.

Main Methods:

  • Identification of Mdmx-binding proteins, including 14-3-3 proteins.
  • Site-directed mutagenesis to create S367A Mdmx mutant.
  • Transfection assays to assess p53 transcriptional activity.
  • Analysis of Mdmx ubiquitination and degradation.
  • Assessment of Mdmx phosphorylation and binding to 14-3-3 after DNA damage.

Main Results:

  • 14-3-3 proteins bind to Mdmx via a consensus sequence involving S367.
  • S367A mutation enhances Mdmx's repression of p53 activity and Mdmx stability.
  • Mdmx phosphorylated at S367 is preferentially degraded by Mdm2.
  • DNA damage induces S367 phosphorylation, increasing 14-3-3 binding and Mdmx degradation.
  • S367 mutation promotes fibroblast growth, indicating enhanced Mdmx activity.

Conclusions:

  • Mdmx phosphorylation at S367 is crucial for p53 activation following DNA damage.
  • S367 phosphorylation triggers Mdm2-dependent Mdmx degradation, releasing p53.
  • This mechanism represents a key cellular defense pathway against cancer.

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