Cell-to-cell variation in p53 dynamics leads to fractional killing.
Open accessAbstract
Many chemotherapeutic drugs kill only a fraction of cancer cells, limiting their efficacy. We used live-cell imaging to investigate the role of p53 dynamics in fractional killing of colon cancer cells in response to chemotherapy. We found that both surviving and dying cells reach similar levels of p53, indicating that cell death is not determined by a fixed p53 threshold. Instead, a cell's probability of death depends on the time and levels of p53. Cells must reach a threshold level of p53 to execute apoptosis, and this threshold increases with time. The increase in p53 apoptotic threshold is due to drug-dependent induction of anti-apoptotic genes, predominantly in the inhibitors of apoptosis (IAP) family. Our study underlines the importance of measuring the dynamics of key players in response to chemotherapy to determine mechanisms of resistance and optimize the timing of combination therapy.
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The dynamics of p53 expression determine cell fate choice, with low-amplitude pulsed expression mediating cell cycle arrest and sustained, high-level expression driving apoptosis.
“The dynamics of p53 expression determine cell fate choice, with low-amplitude pulsed expression mediating cell cycle arrest and sustained, high-level expression driving apoptosis.28”
From Pharmacokinetic-pharmacodynamic-efficacy modeling of the MDM2 inhibitor brigimadlin in glioblastoma patient-derived xenografts (2026) · cites this paper as [28]
The Introduction (page unavailable) reports that pulsed p53 favors cell-cycle arrest genes and sustained p53 favors apoptotic genes. But the Results (‘Rapid accumulation of p53 is associated with cell death’; page unavailable) found that maximum p53 levels did not differ between apoptotic and surviving cells: faster accumulation, rather than sustained high-level expression alone, was associated with death. The claimed pairing of low-amplitude pulses with arrest and sustained high levels with apoptosis therefore overstates this paper’s findings. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe switch between cell cycle arrest and apoptosis in response to DNA damage is largely dictated by the cell reaching threshold p53 protein levels.
“The switch between cell cycle arrest and apoptosis in response to DNA damage, is largely dictated by the cell reaching threshold p53 protein levels (Kracikova et al., 2013; Paek et al., 2016).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Paek et al., 2016
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References 62 · Cited by 292
Research works printed but not linked: 2
- Hoffmann A Levchenko A Scott ML Baltimore D The IkappaB-NFkappaB signaling module: temporal control and selective gene activation Science 2002 298 1241 1245 12424381
- Hussner J Ameling S Hammer E Herzog S Steil L Schwebe M Niessen J Schroeder HW Kroemer HK Ritter CA Regulation of Interferoninducible Proteins by Doxorubicin via IFNγ-JAK-STAT Signaling in Tumor Cells Mol. Pharmacol 2012 22323498
- Authors
- Paek, A. L., Liu, J. C., Loewer, A., Forrester, W. C., & Lahav, G.
- Affiliations
- Harvard University (US)
- Corresponding author
- Lahav, Galit
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 165
- Issue
- 3
- Pages
- 631-642
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5217463
- OpenAlex
- W2321162622
- Cited by
- 292
- References
- 62
- Citations by year
- 2026: 10 · 2025: 25 · 2024: 22 · 2023: 24 · 2022: 23 · 2021: 37 · 2020: 32 · 2019: 52 · 2018: 31 · 2017: 25 · 2016: 10
- FWCI
- 21.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Novartis Repository (Novartis) (submittedVersion)
- Funders
- Novartis Institutes for Biomedical Research
- NIH (GM083303)
- American Cancer Society New England Division-Ellison Foundation Postdoctoral Fellowship
- NIH/NIGMS (T32008313)
- National Science Foundation Graduate Research Fellowship
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- chemoresistance, colon cancer, apoptosis, inhibitor of apoptosis proteins, anti-apoptotic genes, cell-to-cell variability, live-cell imaging
- MeSH terms
- Antineoplastic Agents, Cisplatin, Humans, Up-Regulation, Tumor Suppressor Protein p53, Apoptosis, Drug Resistance, Neoplasm, Cell Line, Tumor, Inhibitor of Apoptosis Proteins
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