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MDM2, MDMX, and p73 regulate cell-cycle progression in the absence of wild-type p53

Alyssa M Klein1,2, Lynn Biderman1, David Tong1

  • 1Department of Biological Sciences, Columbia University, New York, NY 10027.

Proceedings of the National Academy of Sciences of the United States of America
|October 30, 2021
PubMed

Insights

The Murine Double Minute 2-Murine Double Double Minute X (MDM2-MDMX) complex regulates cell-cycle progression independently of p53. Inhibiting MDM2-MDMX or p73 causes cell-cycle arrest, suggesting new cancer targets.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cell Biology

Background:

  • The p53 tumor suppressor protein is crucial for cell-cycle arrest and apoptosis.
  • The Murine Double Minute 2-Murine Double Minute X (MDM2-MDMX) heterodimer is a key regulator of p53.
  • MDM2-MDMX's role in p53-mediated cell-cycle regulation is well-established.

Purpose of the Study:

  • To investigate the p53-independent functions of the MDM2-MDMX complex.
  • To explore the role of MDM2-MDMX in cell-cycle progression in the absence of functional p53.
  • To identify potential therapeutic targets in cancers with non-wild-type p53.

Main Methods:

  • Studied cells lacking p53 or expressing mutant p53.
  • Assessed the effects of MDM2/MDMX loss or E3 ligase inhibition on cell-cycle arrest.
  • Analyzed the impact on E2F1, E2F3, and p73 protein and mRNA levels.
  • Investigated the consequences of p73 ablation on cell-cycle progression and E2F expression.

Main Results:

  • Loss of MDM2/MDMX or inhibition of their E3 ligase activity induced cell-cycle arrest in p53-deficient or mutant cells.
  • This arrest correlated with reduced levels of E2F1, E2F3, and p73.
  • Directly ablating p73 mimicked these effects on the cell cycle and E2F family member expression.
  • MDM2-MDMX appears to promote E2F family member and p73 activity in a p53-independent manner.

Conclusions:

  • The MDM2-MDMX complex plays a significant p53-independent role in maintaining cell-cycle progression.
  • This function involves promoting the activity of E2F family members and p73.
  • MDM2-MDMX represents a potential therapeutic target in cancers lacking wild-type p53.
Keywords:
E2F1MDM2MDMXcell cyclep73

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