Cited by 335Cancer-related Molecular PathwaysGene Regulatory Network AnalysisMathematical Biology Tumor Growth

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Two-phase dynamics of p53 in the DNA damage response

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Zhang, Xiao-Peng, Liu, Feng, Wang, Wei·2011·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1100600108PMC PMC3107314

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Abstract

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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Authors: Zhang, X.-P., Liu, F., & Wang, W.
Affiliations: National Laboratory of Solid State Microstructures (CN)
University of California System (US)
ORCID: Zhang, Xiao-Peng
Liu, Feng
Wang, Wei
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
DOI: 10.1073/pnas.1100600108
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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Two-phase dynamics of p53 in the DNA damage response

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