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Oncogenic alterations in the p53 pathway abolish oscillatory competence

View ORCID ProfileLingyun Xiong, Alan Garfinkel
doi: https://doi.org/10.1101/2021.02.09.430245
Lingyun Xiong
1MPLS Doctoral Training Centre, University of Oxford, Oxford, OX1 3NP, UK
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  • ORCID record for Lingyun Xiong
Alan Garfinkel
2Departments of Medicine (Cardiology) and Integrative Biology and Physiology, University of California, Los Angeles, CA 90095 USA
32019-2020 Newton Abraham Visiting Professor, University of Oxford, Oxford, OX1 3DR, UK
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  • For correspondence: agarfinkel@mednet.ucla.edu
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Abstract

The tumor suppressor p53 displays concentration oscillations in response to DNA damage, a behavior that has been suggested to be essential to its anti-cancer function. Many genetic alterations in the p53 pathway have been shown to be oncogenic, whether by experiment or by clinical associations with various cancers. These oncogenic alterations include somatic mutations, copy number variations and inherited polymorphisms. Using a differential equation model of p53-Mdm2 dynamics, we employ Hopf bifurcation analysis to show that all of the oncogenic perturbations have a common effect, to abolish the oscillatory competence of p53, thereby impairing its tumor suppressor function. In this analysis, these diverse genetic alterations, widely observed in human cancers, have a unified mechanistic explanation.

Significance In human cancers, the p53 tumor suppressor pathway is frequently altered by diverse genetic changes. An integrated understanding of these oncogenic alterations is currently lacking. We show that all oncogenic alterations in the p53 pathway abolish the oscillatory competence of p53, a property that is essential for cell cycle arrest upon stress, for effective DNA damage response and for maintaining genome integrity. This unified dynamical explanation of distinct cancer driver events that converge on a key cancer hallmark pathway has practical implications for anti-cancer therapies.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted February 10, 2021.
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Oncogenic alterations in the p53 pathway abolish oscillatory competence
Lingyun Xiong, Alan Garfinkel
bioRxiv 2021.02.09.430245; doi: https://doi.org/10.1101/2021.02.09.430245
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Oncogenic alterations in the p53 pathway abolish oscillatory competence
Lingyun Xiong, Alan Garfinkel
bioRxiv 2021.02.09.430245; doi: https://doi.org/10.1101/2021.02.09.430245

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