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Modeling the Basal Dynamics of P53 System

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  • Tingzhe Sun
  • Weiwei Yang
  • Jing Liu
  • Pingping Shen

Abstract

Background: The tumor suppressor p53 has become one of most investigated genes. Once activated by stress, p53 leads to cellular responses such as cell cycle arrest and apoptosis. Methodology/Principal Findings: Most previous models have ignored the basal dynamics of p53 under nonstressed conditions. To explore the basal dynamics of p53, we constructed a stochastic delay model by incorporating two negative feedback loops. We found that protein distribution of p53 under nonstressed condition is highly skewed with a fraction of cells showing high p53 levels comparable to those observed under stressed conditions. Under nonstressed conditions, asynchronous and spontaneous p53 pulses are triggered by basal DNA double strand breaks produced during normal cell cycle progression. The first peaking times show a predominant G1 distribution while the second ones are more widely distributed. The spontaneous pulses are triggered by an excitable mechanism. Once initiated, the amplitude and duration of pulses remain unchanged. Furthermore, the spontaneous pulses are filtered by ataxia telangiectasia mutated protein mediated posttranslational modifications and do not result in substantial p21 transcription. If challenged by externally severe DNA damage, cells generate synchronous p53 pulses and induce significantly high levels of p21. The high expression of p21 can also be partially induced by lowering the deacetylation rate. Conclusions: Our results demonstrated that the dynamics of p53 under nonstressed conditions is initiated by an excitable mechanism and cells become fully responsive only when cells are confronted with severe damage. These findings advance our understanding of the mechanism of p53 pulses and unlock many opportunities to p53-based therapy.

Suggested Citation

  • Tingzhe Sun & Weiwei Yang & Jing Liu & Pingping Shen, 2011. "Modeling the Basal Dynamics of P53 System," PLOS ONE, Public Library of Science, vol. 6(11), pages 1-9, November.
  • Handle: RePEc:plo:pone00:0027882
    DOI: 10.1371/journal.pone.0027882
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    References listed on IDEAS

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    1. Christopher J. Bakkenist & Michael B. Kastan, 2003. "DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation," Nature, Nature, vol. 421(6922), pages 499-506, January.
    2. Arjun Raj & Charles S Peskin & Daniel Tranchina & Diana Y Vargas & Sanjay Tyagi, 2006. "Stochastic mRNA Synthesis in Mammalian Cells," PLOS Biology, Public Library of Science, vol. 4(10), pages 1-13, September.
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    1. Richard Moore & Hsu Kiang Ooi & Taek Kang & Leonidas Bleris & Lan Ma, 2015. "MiR-192-Mediated Positive Feedback Loop Controls the Robustness of Stress-Induced p53 Oscillations in Breast Cancer Cells," PLOS Computational Biology, Public Library of Science, vol. 11(12), pages 1-17, December.

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