Regulation of p53: a collaboration between Mdm2 and Mdmx

Oncotarget. 2012 Mar;3(3):228-35. doi: 10.18632/oncotarget.443.


p53 plays an important role in the regulation of the cell cycle, DNA repair, and apoptosis and is an attractive cancer therapeutic target. Mdm2 and Mdmx are recognized as the main p53 negative regulators. Although it remains unclear why Mdm2 and Mdmx are both required for p53 degradation, a model has been proposed whereby these two proteins function independent of one another; Mdm2 acts as an E3 ubiquitin ligase that catalyzes the ubiquitination of p53 for degradation, whereas Mdmx inhibits p53 by binding to and masking the transcriptional activation domain of p53, without causing its degradation. However, Mdm2 and Mdmx have been shown to function collaboratively. In fact, recent studies have pointed to a more important role for an Mdm2/Mdmx co-regulatory mechanism of p53 regulation than previously thought. In this review, we summarize current progress in the field about the functional and physical interaction between Mdm2 and Mdmx, their individual and collaborative roles in controlling p53, and inhibitors that target Mdm2 and Mdmx as a novel class of anticancer therapeutics.

Publication types

  • Review

MeSH terms

  • Animals
  • Cell Cycle Proteins
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Models, Biological
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Protein Processing, Post-Translational / genetics
  • Protein Processing, Post-Translational / physiology
  • Protein Stability
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Proto-Oncogene Proteins c-mdm2 / physiology*
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Protein p53 / physiology
  • Ubiquitination / genetics
  • Ubiquitination / physiology


  • Cell Cycle Proteins
  • MDM4 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2