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Modeling the role of p53 pulses in DNA damage- induced cell death decision.

Sun T, Chen C, Wu Y, Zhang S, Cui J, Shen P - BMC Bioinformatics (2009)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China. confucian007@126.com

ABSTRACT

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.

Conclusion: 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.

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Illustration of the counting mechanism. The steady state is shown. (solid grey: stable steady state; dotted grey: unstable steady state. p4 = 0.002). The corresponding values of the steady state are shown as indicated in Figure 2C (0.008, 0.050, 0.328 μM from bottom to top). Dotted blue arrows indicate the equilibrium concentrations. The threshold level is indicated at the text box. Solid black arrows represent the Bax concentration reached during each pulse of p53. Temporal responses of oligomerized Bax (solid red) and PUMA (dashed violet) are shown.
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Figure 6: Illustration of the counting mechanism. The steady state is shown. (solid grey: stable steady state; dotted grey: unstable steady state. p4 = 0.002). The corresponding values of the steady state are shown as indicated in Figure 2C (0.008, 0.050, 0.328 μM from bottom to top). Dotted blue arrows indicate the equilibrium concentrations. The threshold level is indicated at the text box. Solid black arrows represent the Bax concentration reached during each pulse of p53. Temporal responses of oligomerized Bax (solid red) and PUMA (dashed violet) are shown.

Mentions: Then we further illustrated the underlying counting mechanism (Figure 6, for IR = 20 Gy). The steady state values of Bax were indicated by arrows in Figure 2C (Three steady states in Figure 2C indicated by arrows correspond to dark grey lines in Figure 6, where solid lines mean stable steady state and dotted line means unstable steady state). Dotted blue arrows show directions of evolution. In the first p53 pulse, transcription of PUMA quickly begins. The level of PUMA rises and falls, which we called it a 'PUMA boosting'. The 'Enabler' PUMA is sensed by Bax activation switch. The new-coming PUMA perturbs Bax activation switch and dissociates 'Activator' (e.g. Bid) from the sequestration of Bcl-2 (and/or other Bcl-2 anti-apoptotics) and then these liberated 'Activator' directly activate Bax. Activated Bax then oligomerizes and contributes to elevated levels of Bax oligomers. When degradation rate of PUMA overrides the production owing to reduced transcription, the levels of PUMA decay. PUMA is then neutralized by newly synthesized Bcl-2 (and/or other anti-apoptotics). In turn Bax oligomers decrease due to degradation and oligomers dissociation. The level of Bax oligomers is a bit higher ([Baxolig] = 0.019 μM) than the original steady state (0.008 μM) at the time when a second PUMA boosting is encountered. Bax oligomers is accumulated but still below the threshold ([Baxolig] = 0.035 μM) at the end of the second PUMA boosting. A third p53 pulse evokes a third PUMA boosting and Bax oligomers further accumulate to surmount the threshold. Once Bax oligomers are above the threshold, they will not decrease and stay at the high steady state. Bax oligomers disrupt mitochondria outer membrane and unleash cytochrome c, which then leads the activation of caspase-3 ensuing apoptosis. Thus, the information on DNA damage is successfully transferred to the Bax activation switch, and the cell death decision has been made irreversibly.


Modeling the role of p53 pulses in DNA damage- induced cell death decision.

Sun T, Chen C, Wu Y, Zhang S, Cui J, Shen P - BMC Bioinformatics (2009)

Illustration of the counting mechanism. The steady state is shown. (solid grey: stable steady state; dotted grey: unstable steady state. p4 = 0.002). The corresponding values of the steady state are shown as indicated in Figure 2C (0.008, 0.050, 0.328 μM from bottom to top). Dotted blue arrows indicate the equilibrium concentrations. The threshold level is indicated at the text box. Solid black arrows represent the Bax concentration reached during each pulse of p53. Temporal responses of oligomerized Bax (solid red) and PUMA (dashed violet) are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2713228&req=5

Figure 6: Illustration of the counting mechanism. The steady state is shown. (solid grey: stable steady state; dotted grey: unstable steady state. p4 = 0.002). The corresponding values of the steady state are shown as indicated in Figure 2C (0.008, 0.050, 0.328 μM from bottom to top). Dotted blue arrows indicate the equilibrium concentrations. The threshold level is indicated at the text box. Solid black arrows represent the Bax concentration reached during each pulse of p53. Temporal responses of oligomerized Bax (solid red) and PUMA (dashed violet) are shown.
Mentions: Then we further illustrated the underlying counting mechanism (Figure 6, for IR = 20 Gy). The steady state values of Bax were indicated by arrows in Figure 2C (Three steady states in Figure 2C indicated by arrows correspond to dark grey lines in Figure 6, where solid lines mean stable steady state and dotted line means unstable steady state). Dotted blue arrows show directions of evolution. In the first p53 pulse, transcription of PUMA quickly begins. The level of PUMA rises and falls, which we called it a 'PUMA boosting'. The 'Enabler' PUMA is sensed by Bax activation switch. The new-coming PUMA perturbs Bax activation switch and dissociates 'Activator' (e.g. Bid) from the sequestration of Bcl-2 (and/or other Bcl-2 anti-apoptotics) and then these liberated 'Activator' directly activate Bax. Activated Bax then oligomerizes and contributes to elevated levels of Bax oligomers. When degradation rate of PUMA overrides the production owing to reduced transcription, the levels of PUMA decay. PUMA is then neutralized by newly synthesized Bcl-2 (and/or other anti-apoptotics). In turn Bax oligomers decrease due to degradation and oligomers dissociation. The level of Bax oligomers is a bit higher ([Baxolig] = 0.019 μM) than the original steady state (0.008 μM) at the time when a second PUMA boosting is encountered. Bax oligomers is accumulated but still below the threshold ([Baxolig] = 0.035 μM) at the end of the second PUMA boosting. A third p53 pulse evokes a third PUMA boosting and Bax oligomers further accumulate to surmount the threshold. Once Bax oligomers are above the threshold, they will not decrease and stay at the high steady state. Bax oligomers disrupt mitochondria outer membrane and unleash cytochrome c, which then leads the activation of caspase-3 ensuing apoptosis. Thus, the information on DNA damage is successfully transferred to the Bax activation switch, and the cell death decision has been made irreversibly.

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, PR China. confucian007@126.com

ABSTRACT

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.

Conclusion: 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.

Show MeSH
Related in: MedlinePlus