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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

Interplay between MDM2, MDMX, Pirh2 and COP1: the negative regulators of p53

Lan Wang1, Guifen He, Pingzhao Zhang

  • 1State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200433, People's Republic of China.

Molecular Biology Reports
|March 25, 2010
PubMed

Insights

MDM2, Pirh2, COP1, and MDMX E3 ligases interact and regulate each other, independently of p53. These proteins synergistically inhibit p53 activity and alter their own protein levels.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Biochemistry

Background:

  • MDM2, Pirh2, and COP1 are E3 ubiquitin ligases targeting p53 for degradation.
  • MDMX inhibits p53 transcriptional activity.
  • Interactions among MDM2, MDMX, Pirh2, and COP1 were previously unreported, except for MDM2-MDMX.

Purpose of the Study:

  • To investigate the interactions between MDM2, MDMX, Pirh2, and COP1.
  • To elucidate the functional consequences of these interactions on p53.
  • To explore the synergistic effects of these proteins on p53 regulation.

Main Methods:

  • Co-transfection experiments to assess protein interactions and levels.
  • Analysis of MDM2 RING finger domain integrity.
  • Assessment of p53-mediated transcriptional activity.
  • Ubiquitination assays for MDM2 and MDMX.

Main Results:

  • MDM2, MDMX, Pirh2, and COP1 interact independently of p53.
  • Co-transfection of any two proteins altered their individual protein levels.
  • MDM2 RING finger domain integrity is essential for elevating COP1 and Pirh2 levels.
  • These four proteins synergistically inhibit p53 transcriptional activity.
  • COP1 inhibits MDM2 self-ubiquitination and MDMX ubiquitination by MDM2.

Conclusions:

  • MDM2, MDMX, Pirh2, and COP1 form a complex that regulates p53.
  • These proteins likely collaborate to inhibit p53 activity in vivo.
  • The findings reveal a novel regulatory network impacting p53 stability and function.

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