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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.

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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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Schematic illustration of the mechanism of digital and sustained oscillation. The upper curve is a bifurcation diagram, p53 versus concentration of activated ATM. The lower curve is the dependence of activated ATM on the damage levels. The parameter k5 donates basal unrepaired DNA damage ([ATM*]: activated ATM. The limit point for the mutant switch is 7.11, for non-mutant switch 9.10).
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Figure 4: Schematic illustration of the mechanism of digital and sustained oscillation. The upper curve is a bifurcation diagram, p53 versus concentration of activated ATM. The lower curve is the dependence of activated ATM on the damage levels. The parameter k5 donates basal unrepaired DNA damage ([ATM*]: activated ATM. The limit point for the mutant switch is 7.11, for non-mutant switch 9.10).

Mentions: We further investigated the underlying mechanism that discriminates the sustained oscillation from the digital oscillation (Figure 4). The parameter k5 donates basal level of DSBs. We set k5 = 1 which highlights a physiological damage, primarily because even in the absence of external stimuli, there appear to be constant, significant levels of physiological DNA damage [29]. Higher assigned values correspond to pathological circumstances (e.g. tumor cells) in our simulations. In physiological conditions (k5 = 1), once DSB levels transcend the threshold (DSB = 9.10), ATM* dramatically flips from low to high state and rapidly becomes fully activated. As DSB is repaired, the levels of ATM* slowly decrease, while an abrupt decline occurs when DSB level falls below the limit point (DSB = 1.22), and then the switch turns off. The duration of high levels of ATM*, which is indicative of the duration of damage repair process, determines the duration time that p53 spends in the oscillatory region. A longer duration in the oscillatory region corresponds to more DSBs and more p53 pulses. This phenomenon finally ensures the digital oscillations in context of different external stimuli. In pathological conditions, however, the ATM functionally becomes a one-way switch (see Figure 4, k5 = 3). An external super-threshold irradiation dose (DSB > 7.11) results in the elevation of ATM* level and turns on the switch. Once fully activated, ATM* never falls down albeit external DSBs are fully repaired (See Figure 3D). The sustained high levels of ATM* 'tell' p53 to oscillate permanently and p53 accepts that idea with no doubt because it has limited knowledge of what is happening on upstream breaks repair process. This ensures a sustained p53 oscillation. Similar results also emerged in other cases (data not shown). Experimental results by Olivier et al. have proved that some tumor cell lines have defective or relaxed checkpoint control and tolerate unrepaired DNA lesions[30]. Overall, these results suggest that a physiologically low level of basal DNA damage defines a hysteretic response of ATM* and digital oscillations of p53, while in pathological conditions, ATM activation becomes a one-way switch and cannot revert to its initial level once activated. These two cases are determined by the basal DSBs. Experiments by Geva-Zatorsky et al. are based on MCF7 breast cancer cells and the observation that p53 performs sustained oscillation is probably ascribed to the significant levels of basal DNA lesions in tumor cell lines[18]. Our assumptions are consistent with experimental results.


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)

Schematic illustration of the mechanism of digital and sustained oscillation. The upper curve is a bifurcation diagram, p53 versus concentration of activated ATM. The lower curve is the dependence of activated ATM on the damage levels. The parameter k5 donates basal unrepaired DNA damage ([ATM*]: activated ATM. The limit point for the mutant switch is 7.11, for non-mutant switch 9.10).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Schematic illustration of the mechanism of digital and sustained oscillation. The upper curve is a bifurcation diagram, p53 versus concentration of activated ATM. The lower curve is the dependence of activated ATM on the damage levels. The parameter k5 donates basal unrepaired DNA damage ([ATM*]: activated ATM. The limit point for the mutant switch is 7.11, for non-mutant switch 9.10).
Mentions: We further investigated the underlying mechanism that discriminates the sustained oscillation from the digital oscillation (Figure 4). The parameter k5 donates basal level of DSBs. We set k5 = 1 which highlights a physiological damage, primarily because even in the absence of external stimuli, there appear to be constant, significant levels of physiological DNA damage [29]. Higher assigned values correspond to pathological circumstances (e.g. tumor cells) in our simulations. In physiological conditions (k5 = 1), once DSB levels transcend the threshold (DSB = 9.10), ATM* dramatically flips from low to high state and rapidly becomes fully activated. As DSB is repaired, the levels of ATM* slowly decrease, while an abrupt decline occurs when DSB level falls below the limit point (DSB = 1.22), and then the switch turns off. The duration of high levels of ATM*, which is indicative of the duration of damage repair process, determines the duration time that p53 spends in the oscillatory region. A longer duration in the oscillatory region corresponds to more DSBs and more p53 pulses. This phenomenon finally ensures the digital oscillations in context of different external stimuli. In pathological conditions, however, the ATM functionally becomes a one-way switch (see Figure 4, k5 = 3). An external super-threshold irradiation dose (DSB > 7.11) results in the elevation of ATM* level and turns on the switch. Once fully activated, ATM* never falls down albeit external DSBs are fully repaired (See Figure 3D). The sustained high levels of ATM* 'tell' p53 to oscillate permanently and p53 accepts that idea with no doubt because it has limited knowledge of what is happening on upstream breaks repair process. This ensures a sustained p53 oscillation. Similar results also emerged in other cases (data not shown). Experimental results by Olivier et al. have proved that some tumor cell lines have defective or relaxed checkpoint control and tolerate unrepaired DNA lesions[30]. Overall, these results suggest that a physiologically low level of basal DNA damage defines a hysteretic response of ATM* and digital oscillations of p53, while in pathological conditions, ATM activation becomes a one-way switch and cannot revert to its initial level once activated. These two cases are determined by the basal DSBs. Experiments by Geva-Zatorsky et al. are based on MCF7 breast cancer cells and the observation that p53 performs sustained oscillation is probably ascribed to the significant levels of basal DNA lesions in tumor cell lines[18]. Our assumptions are consistent with experimental results.

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