Cell type–dependent bimodal p53 activation engenders a dynamic mechanism of chemoresistance

Ruizhen Yang, Bo Huang, Yanting Zhu, Yang Li, Feng Liu*, Jue SHI

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)

Abstract

Studies of drug resistance mostly characterize genetic mutation, and we know much less about phenotypic mechanisms of drug resistance, especially at a quantitative level. p53 is an important mediator of cellular response to chemotherapy, but even p53 wild-type cells vary in drug sensitivity for unclear reasons. Here, we elucidated a new resistance mechanism to a DNA-damaging chemotherapeutic through bimodal modulation of p53 activation dynamics. By combining single-cell imaging with computational modeling, we characterized a four-component regulatory module, which generates bimodal p53 dynamics through coupled feed-forward and feedback, and found that the inhibitory strength between ATM and Mdm2 determined the differential modular output between drug-sensitive and drug-resistant cancer cell lines. We further showed that the combinatorial inhibition of Mdm2 and Wip1 was an effective strategy to alter p53 dynamics in resistant cancer cells and sensitize their apoptotic response. Our results point to p53 pulsing as a potentially druggable mechanism that mediates chemoresistance.

Original languageEnglish
Article numbereaat5077
JournalScience advances
Volume4
Issue number12
DOIs
Publication statusPublished - 19 Dec 2018

Scopus Subject Areas

  • General

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