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Cytoplasmic tethering is involved in synergistic inhibition of p53 by Mdmx and Mdm2

Chihiro Ohtsubo1, Daisuke Shiokawa, Masami Kodama

  • 1Radiobiology Division, National Cancer Center Research Institute, Tokyo, Japan.

Cancer Science
|May 13, 2009
PubMed

Insights

MDM2 and MDMX oncogenes synergistically inactivate p53. This study reveals MDMX sequesters p53 in the cytoplasm, enhancing its inactivation by MDM2, a key mechanism in some cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The MDM2 and MDMX oncogenes are crucial for the synergistic inactivation of the tumor suppressor p53.
  • The precise mechanism by which MDMX enhances MDM2's inhibition of p53 remains unclear.

Purpose of the Study:

  • To elucidate the biochemical mechanism of MDMX-MDM2 synergistic p53 inactivation.
  • To investigate the role of subcellular localization of MDMX in p53 regulation.

Main Methods:

  • Utilized nonphosphorylatable and subcellular localization mutants of MDMX.
  • Employed RNA interference (RNAi) to inhibit MDMX expression.
  • Assessed p53 localization, interaction with MDM2/MDMX, and ubiquitination in neuroblastoma cells.

Main Results:

  • Cooperative inhibition of p53 by MDMX and MDM2 correlated with p53's cytoplasmic localization and increased MDMX-p53-MDM2 interactions in the cytoplasm.
  • MDMX and MDM2 induced p53 ubiquitination at C-terminal lysine residues, partly dependent on lysine integrity.
  • Cytoplasmic MDMX tethered p53, inhibiting its activity; nuclear localization mutants of MDMX reduced cytoplasmic p53 retention.

Conclusions:

  • Cytoplasmic sequestration of p53 by MDMX is a significant contributor to p53 inactivation in certain cancer cells.
  • MDMX's subcellular localization dictates p53 localization and activity, highlighting a novel mechanism of tumor suppression evasion.

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