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Phosphorylation of MDMX mediated by Akt leads to stabilization and induces 14-3-3 binding

Vanessa Lopez-Pajares1, Mihee M Kim, Zhi-Min Yuan

  • 1Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

The Journal of Biological Chemistry
|March 22, 2008
PubMed

Insights

The Akt kinase stabilizes MDMX by phosphorylating it, which in turn stabilizes MDM2. This pathway offers a new target for cancer therapies by affecting the tumor suppressor p53.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The tumor suppressor p53 is crucial for preventing cancer but is often inactivated in tumors.
  • The MDM2-MDMX complex is essential for degrading p53.
  • Understanding regulatory mechanisms of MDM2-MDMX is vital for cancer therapy.

Purpose of the Study:

  • To investigate the interaction between MDMX and other proteins.
  • To elucidate the role of Akt kinase in regulating MDMX.
  • To understand the implications for p53 stability and cancer progression.

Main Methods:

  • Co-immunoprecipitation assays to identify binding partners.
  • Phosphorylation site mapping.
  • Western blotting to assess protein stabilization.
  • Kinase assays to determine enzyme activity.

Main Results:

  • 14-3-3 protein identified as a novel binding partner of MDMX.
  • Akt kinase phosphorylates MDMX at Ser367 in a phosphorylation-dependent manner.
  • Phosphorylation of MDMX by Akt leads to MDMX stabilization and subsequent MDM2 stabilization.
  • This represents an alternative mechanism for Akt to up-regulate MDM2 levels.

Conclusions:

  • Akt-mediated phosphorylation of MDMX is a key event in stabilizing the MDM2-MDMX complex.
  • This pathway contributes to the oncogenic function of Akt by inactivating p53.
  • Targeting this Akt-MDMX interaction could offer new therapeutic strategies for cancers with p53 pathway alterations.

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