Fluctuations in p53 Signaling Allow Escape from Cell-Cycle Arrest
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Biological signals need to be robust and filter small fluctuations yet maintain sensitivity to signals across a wide range of magnitudes. Here, we studied how fluctuations in DNA damage signaling relate to maintenance of long-term cell-cycle arrest. Using live-cell imaging, we quantified division profiles of individual human cells in the course of 1 week after irradiation. We found a subset of cells that initially establish cell-cycle arrest and then sporadically escape and divide. Using fluorescent reporters and mathematical modeling, we determined that fluctuations in the oscillatory pattern of the tumor suppressor p53 trigger a sharp switch between p21 and CDK2, leading to escape from arrest. Transient perturbation of p53 stability mimicked the noise in individual cells and was sufficient to trigger escape from arrest. Our results show that the self-reinforcing circuitry that mediates cell-cycle transitions can translate small fluctuations in p53 signaling into large phenotypic changes.
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Inactivation of p21 allows human senescing fibroblasts to override senescence arrest and extends their proliferative potential, probably because in these cells CDK2 activity cannot be sufficiently reduced.
“Inactivation of p21 allows human senescing fibroblasts to override senescence arrest and extends their proliferative potential, probably because in these cells CDK2 activity cannot be sufficiently reduced [41,42].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [42]
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- Authors
- Reyes, J., Chen, J.-Y., Stewart-Ornstein, J., Karhohs, K. W., Mock, C. S., & Lahav, G.
- Affiliations
- Harvard University (US)
- Corresponding author
- Lahav, Galit
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2018-08
- Volume
- 71
- Issue
- 4
- Pages
- 581-591.e5
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC6282757
- OpenAlex
- W2883592521
- Cited by
- 149
- References
- 50
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 16 · 2023: 18 · 2022: 21 · 2021: 20 · 2020: 23 · 2019: 18 · 2018: 3
- FWCI
- 6.00
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-03-21)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (GM116864, GM107618, CA207727)
- CONACyT/Fundacion Mexico en Harvard (404476)
- Harvard Graduate Merit Fellowship
- Jane Coffin Child Memorial Fund for Medical Research
- The Jane Coffin Childs Memorial Fund for Medical Research
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Keywords
- p53 pathway, cell cycle arrest, DNA damage response, stochastic fluctuations, p21, CDK2, p53 stabilization, cell division, cell cycle transition
- MeSH terms
- Red Fluorescent Protein, Cell Division, Cell Line, Transformed, DNA Damage, Epithelial Cells, Gamma Rays, Gene Expression Regulation, Humans, Luminescent Proteins, Models, Statistical, Signal Transduction, Tumor Suppressor Protein p53, Genes, Reporter, RNA, Small Interfering, Cell Proliferation, Green Fluorescent Proteins, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase 2, Retinal Pigment Epithelium, Protein Stability, Time-Lapse Imaging, Cell Cycle Checkpoints
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