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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

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A common pathway to cancer: Oncogenic mutations abolish p53 oscillations

Lingyun Xiong1, Alan Garfinkel2

  • 1Department of Stem Cell Biology and Regenerative Medicine, University of Southern California, Los Angeles, CA 90007 USA; Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, 90007, USA; Ludwig Institute for Cancer Research, University of Oxford, Oxford, OX3 7DQ, UK.

Progress in Biophysics and Molecular Biology
|June 25, 2022
PubMed

Insights

Genetic alterations in human cancers abolish the essential DNA damage-induced oscillations of tumor suppressor p53, impairing its anti-cancer function. This study unifies the mechanistic explanation for diverse cancer-associated p53 pathway alterations.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Systems Biology

Background:

  • The tumor suppressor p53 plays a critical role in preventing cancer.
  • p53 exhibits oscillations in response to DNA double-strand breaks, a behavior linked to its anti-cancer function.
  • Genetic alterations in the p53 pathway are prevalent in human cancers and can be oncogenic.

Purpose of the Study:

  • To investigate the common mechanistic basis for diverse genetic alterations in the p53 pathway observed in human cancers.
  • To determine how these alterations affect the oscillatory behavior of p53 in response to DNA damage.

Main Methods:

  • Utilized a differential equation model to simulate p53-Mdm2 dynamics.
  • Employed Hopf bifurcation analysis to assess the impact of genetic alterations on p53 oscillations.

Main Results:

  • Demonstrated that various cancer-associated genetic alterations commonly abolish the oscillatory competence of p53.
  • Showed that these alterations impair the tumor suppressive function of p53 by disrupting its normal response to DNA damage.

Conclusions:

  • Diverse genetic alterations in the p53 pathway share a unified mechanism of action: disruption of p53 oscillations.
  • This disruption provides a mechanistic explanation for the oncogenic role of these alterations in human cancers.
  • Understanding this unified mechanism can inform cancer diagnosis and therapeutic strategies targeting the p53 pathway.
Keywords:
DNA damage responseHopf bifurcationOncogenic alterationsTumor suppressionp53 oscillations

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