title: Modeling the basal dynamics of p53 system.
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.
  
  
  RESULTS
  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.
authors: State Key Laboratory of Pharmaceutical Biotechnology, Department of Life Sciences, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.
authors: Tingzhe
authors: T
authors: Sun
authors: Weiwei
authors: W
authors: Yang
authors: Jing
authors: J
authors: Liu
authors: Pingping
authors: P
authors: Shen
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003198:Computer Simulation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D008962:Models, Theoretical; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D010766:Phosphorylation; D000071636:Protein Phosphatase 2C; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C