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Two-phase dynamics of p53 in the DNA damage response
Open accessAbstract
The tumor suppressor p53 mainly induces cell cycle arrest/DNA repair or apoptosis in the DNA damage response. How to choose between these two outcomes is not fully understood. We proposed a four-module model of the p53 signaling network and associated the network dynamics with cellular outcomes after ionizing radiation. We found that the cellular response is mediated by both the level and posttranslational modifications of p53 and that p53 is activated in a progressive manner. First, p53 is partially activated by primary modifications such as phosphorylation at Ser-15/20 to induce cell cycle arrest, with its level varying in a series of pulses. If the damage cannot be fixed after a critical number of p53 pulses, then p53 is fully activated by further modifications such as phosphorylation at Ser-46 to trigger apoptosis, with its concentration switching to rather high levels. Thus, p53 undergoes a two-phase response in irreparably damaged cells. Such combinations of pulsatile and switch-like behaviors of p53 may represent a flexible and efficient control mode, avoiding the premature apoptosis and promoting the execution of apoptosis. In our model, p53 pulses are recurrently driven by ataxia telangiectasia mutated (ATM) pulses triggered by DNA damage. The p53-Mdm2 and ATM-p53-Wip1 negative feedback loops are responsible for p53 pulses, whereas the switching behavior occurs when the p53-PTEN-Akt-Mdm2 positive feedback loop becomes dominant. Our results suggest that a sequential predominance of distinct feedback loops may elicit multiple-phase dynamical behaviors. This work provides a new mechanism for p53 dynamics and cell fate decision.
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“TP53 plays a central role in regulating cellular responses to genotoxic stress13–17”
From Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia (2015) · cites this paper as [17]
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Citations
Cites
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“First, p53 is primarily modified (such as phosphorylation at Ser-15 and Ser-20) and accumulates in pulses to induce protective cell cycle arrest for repairable DNA damage; it is further modified (such as phosphorylation at Ser-46) and fully activated to induce apoptosis for irreparable DNA damage (35).”
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Metadata
- Authors
- Zhang, X.-P., Liu, F., & Wang, W.
- Affiliations
- National Laboratory of Solid State Microstructures (CN)
- University of California System (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-05-16
- Volume
- 108
- Issue
- 22
- Pages
- 8990-8995
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3107314
- OpenAlex
- W2058631780
- Cited by
- 333
- References
- 55
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 17 · 2023: 27 · 2022: 31 · 2021: 27 · 2020: 25 · 2019: 27 · 2018: 15 · 2017: 24 · 2016: 14 · 2015: 18 · 2014: 35 · 2013: 21 · 2012: 25
- FWCI
- 13.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (10834002)
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province (BK2009008)
- Program for New Century Excellent Talents in University (NCET-08, NCET-08-0269)
- National Key Research and Development Program of China (2007CB814806)
- 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, DNA damage response, ionizing radiation, cell cycle arrest, apoptosis, post-translational modification, p53 phosphorylation, ATM, MDM2, Wip1, negative feedback loop, cell fate determination, mathematical modeling of gene regulation
- MeSH terms
- DNA Damage, DNA Repair, DNA-Binding Proteins, Humans, Models, Theoretical, Neoplasms, Oscillometry, Phosphorylation, Serine, Time Factors, Signal Transduction, Genes, p53, Tumor Suppressor Protein p53, Apoptosis, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Cell Lineage, Tumor Suppressor Proteins, Ataxia Telangiectasia Mutated Proteins
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