ArticleScience advances2018
Cell type-dependent bimodal p53 activation engenders a dynamic mechanism of chemoresistance.
Article in Science advances, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 43 citations in OpenAlex.
- Design principles for robust multistability in coupled feedforward-feedback regulatory circuits.NPJ systems biology and applications · 2026Article
- Dynamic increases in p53 expression suppress human myoblast differentiation.Frontiers in cell and developmental biology · 2026Article
- Opto-p53: A light-controllable activation of p53 signaling pathway.Cell structure and function · 2025Article
- Cell confluency affects p53 dynamics in response to DNA damage.Molecular biology of the cell · 2025Article
- Systems Biology of the Cancer Cell.Annual review of biomedical engineering · 2025Review
- Linking signaling dynamics and cell fate decisions through single-cell imaging: evidence and challenges.Frontiers in cell and developmental biology · 2025Review
- Complex p53 dynamics regulated by miR-125b in cellular responses to reactive oxidative stress and DNA damage.Briefings in bioinformatics · 2024Article
- Review
- Coordination of MAPK and p53 dynamics in the cellular responses to DNA damage and oxidative stress.Molecular systems biology · 2022Article
- Single-cell analysis of p53 transitional dynamics unravels stimulus- and cell type-dependent signaling output motifs.BMC biology · 2022Article
- A noninvasive iRFP713 p53 reporter reveals dynamic p53 activity in response to irradiation and liver regeneration in vivo.Science signaling · 2022Article
- RIP1-dependent linear and nonlinear recruitments of caspase-8 and RIP3 respectively to necrosome specify distinct cell death outcomes.Protein & cell · 2021Article
- Progress and challenges in understanding the regulation and function of p53 dynamics.Biochemical Society transactions · 2021Review
- Mitochondrial Fuel Dependence on Glutamine Drives Chemo-Resistance in the Cancer Stem Cells of Hepatocellular Carcinoma.International journal of molecular sciences · 2021Article
- Dual roles of SIRT1 in the BAX switch through the P53 module: A mathematical modeling study.Computational and structural biotechnology journal · 2021Article
- p53 EnhancesInternational journal of molecular sciences · 2020Article
- Rucaparib Treatment Alters p53 Oscillations in Single Cells to Enhance DNA-Double-Strand-Break-Induced Cell Cycle Arrest.Cell reports · 2020Article
- Activation of Mitochondrial 2-Oxoglutarate Dehydrogenase by Cocarboxylase in Human Lung Adenocarcinoma Cells A549 Is p53/p21-Dependent and Impairs Cellular Redox State, Mimicking the Cisplatin Action.International journal of molecular sciences · 2020Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.