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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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Related in: MedlinePlus

Dynamics of the integrated model. Upper panel: Time course plot of oligomerized Bax (violet). Lower panel: Time course plot of p53 (blue) and PUMA (green). PUMA levels are gradually accumulated, ratcheting up at each p53 pulse until it reaches a threshold level at which the Bax activation switch turns on (IR = 0.3, 3, and 20 Gy respectively).
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Figure 5: Dynamics of the integrated model. Upper panel: Time course plot of oligomerized Bax (violet). Lower panel: Time course plot of p53 (blue) and PUMA (green). PUMA levels are gradually accumulated, ratcheting up at each p53 pulse until it reaches a threshold level at which the Bax activation switch turns on (IR = 0.3, 3, and 20 Gy respectively).

Mentions: Previous work by our group showed that the Bax activation switch, which computes multiple apoptotic inputs into an all-or-none fashion corresponds to either survival or death [27,28]. However, what signals register DNA damage and then impinge on downstream apoptosis remains unsolved. Here we provided a plausible mechanism by our mathematical simulations (Figure 5). On the left panel (IR = 0.3 Gy), a slight irradiation dose triggers one p53 pulse and the external DSBs are rapidly repaired. Expression level of PUMA increases as p53 becomes activated with a delay, which indicates the time for transcription, translocation and translation. Newly produced PUMA brings perturbation to downstream Bax activation switch and a subtle elevation in Bax oligomers appears but soon tarnishes. Mild perturbation is tolerated, and all components return to their original steady state hours later. A ten-fold irradiation dose (IR = 3 Gy, Figure 5, middle panel) evokes two p53 pulses followed by a step-wise raise in PUMA. The damage is also repaired and Bax oligomers eventually revert to the initial steady state (0.008 μM). In this case, Bax oligomers reach a higher peak value compared with the one under lower irradiation. Also, it takes a longer time for Bax oligomers to return to resting state. A more severe irradiation (IR = 20 gy, row 2 column 3) evokes three pulses, and Bax oligomers have an abrupt onset and finally jump to a high level (0.328 μM). PUMA undergoes a step-wise upswing during each pulse of p53 (Figure 5, right panel).


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)

Dynamics of the integrated model. Upper panel: Time course plot of oligomerized Bax (violet). Lower panel: Time course plot of p53 (blue) and PUMA (green). PUMA levels are gradually accumulated, ratcheting up at each p53 pulse until it reaches a threshold level at which the Bax activation switch turns on (IR = 0.3, 3, and 20 Gy respectively).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Dynamics of the integrated model. Upper panel: Time course plot of oligomerized Bax (violet). Lower panel: Time course plot of p53 (blue) and PUMA (green). PUMA levels are gradually accumulated, ratcheting up at each p53 pulse until it reaches a threshold level at which the Bax activation switch turns on (IR = 0.3, 3, and 20 Gy respectively).
Mentions: Previous work by our group showed that the Bax activation switch, which computes multiple apoptotic inputs into an all-or-none fashion corresponds to either survival or death [27,28]. However, what signals register DNA damage and then impinge on downstream apoptosis remains unsolved. Here we provided a plausible mechanism by our mathematical simulations (Figure 5). On the left panel (IR = 0.3 Gy), a slight irradiation dose triggers one p53 pulse and the external DSBs are rapidly repaired. Expression level of PUMA increases as p53 becomes activated with a delay, which indicates the time for transcription, translocation and translation. Newly produced PUMA brings perturbation to downstream Bax activation switch and a subtle elevation in Bax oligomers appears but soon tarnishes. Mild perturbation is tolerated, and all components return to their original steady state hours later. A ten-fold irradiation dose (IR = 3 Gy, Figure 5, middle panel) evokes two p53 pulses followed by a step-wise raise in PUMA. The damage is also repaired and Bax oligomers eventually revert to the initial steady state (0.008 μM). In this case, Bax oligomers reach a higher peak value compared with the one under lower irradiation. Also, it takes a longer time for Bax oligomers to return to resting state. A more severe irradiation (IR = 20 gy, row 2 column 3) evokes three pulses, and Bax oligomers have an abrupt onset and finally jump to a high level (0.328 μM). PUMA undergoes a step-wise upswing during each pulse of p53 (Figure 5, right panel).

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