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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

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

Published on: August 4, 2019

The RP-Mdm2-p53 pathway and tumorigenesis

Paula L Miliani de Marval1, Yanping Zhang

  • 1Department of Radiation Oncology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Oncotarget
|March 17, 2011
PubMed

Insights

The p53 tumor suppressor pathway is crucial for cell homeostasis. This study reveals that ribosomal protein interactions with Mdm2 are vital for p53

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Biology

Background:

  • The p53 tumor suppressor is a key regulator of cellular homeostasis, responding to various stressors.
  • Ribosomal protein (RP)-mediated suppression of Mdm2 E3 ligase activity activates p53.
  • Mdm2 mutations disrupting RP binding are found in human cancers, but their significance is unclear.

Purpose of the Study:

  • To investigate the in vivo physiological significance of the ribosomal protein-Mdm2 interaction in p53 signaling.
  • To determine if disrupting RP binding to Mdm2 affects the p53 response to ribosomal biogenesis perturbations.

Main Methods:

  • Generation of Mdm2C305F mutant mice with disrupted RPL11 and RPL5 binding.
  • Assessment of p53 response to DNA damage and ribosomal biogenesis inhibition in Mdm2C305F mice.

Main Results:

  • Mdm2C305F mice are viable and maintain a normal p53 response to DNA damage.
  • Mdm2C305F mice exhibit a diminished p53 response to ribosomal biogenesis perturbations.
  • This provides the first in vivo evidence for an RP-Mdm2-p53 signaling pathway.

Conclusions:

  • The interaction between ribosomal proteins and Mdm2 is essential for the p53 pathway's response to ribosomal stress.
  • This pathway's dysregulation may be relevant to human cancer development.

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