Modeling the role of p53 pulses in DNA damage- induced cell death decision.
BACKGROUND
The tumor suppressor p53 plays pivotal roles in tumorigenesis suppression. Although oscillations of p53 have been extensively studied, the mechanism of p53 pulses and their physiological roles in DNA damage response remain unclear.


RESULTS
To address these questions we presented an integrated model in which Ataxia-Telangiectasia Mutated (ATM) activation and p53 oscillation were incorporated with downstream apoptotic events, particularly the interplays between Bcl-2 family proteins. We first reproduced digital oscillation of p53 as the response of normal cells to DNA damage. Subsequent modeling in mutant cells showed that high basal DNA damage is a plausible cause for sustained p53 pulses observed in tumor cells. Further computational analyses indicated that p53-dependent PUMA accumulation and the PUMA-controlled Bax activation switch might play pivotal roles to count p53 pulses and thus decide the cell fate.


CONCLUSIONS
The high levels of basal DNA damage are responsible for generating sustained pulses of p53 in the tumor cells. Meanwhile, the Bax activation switch can count p53 pulses through PUMA accumulation and transfer it into death signal. Our modeling provides a plausible mechanism about how cells generate and orchestrate p53 pulses to tip the balance between survival and death.
Sun
Tingzhe
T
State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China. confucian007@126.com
Chen
Chun
C
Wu
Yuanyuan
Y
Zhang
Shuai
S
Cui
Jun
J
Shen
Pingping
P
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000737:chemistry; D016923:Cell Death; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000737:chemistry; D006801:Humans; D008962:Models, Theoretical; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000737:chemistry; D051028:bcl-2-Associated X Protein / Q000737:chemistry
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; D051736:Proto-Oncogene Proteins c-mdm2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases