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Significance of p53 dynamics in regulating apoptosis in response to ionizing radiation, and polypharmacological strategies.

Liu B, Bhatt D, Oltvai ZN, Greenberger JS, Bahar I - Sci Rep (2014)

Bottom Line: Here we build a stochastic model of p53 induced apoptosis comprised of coupled modules of nuclear p53 activation, mitochondrial cytochrome c release and cytosolic caspase activation that also takes into account cellular heterogeneity.Our simulations show that the strength of p53 transcriptional activity and its coupling (or timing with respect) to mitochondrial pore opening are major determinants of cell fate: for systems where apoptosis is elicited via a p53-transcription-independent mechanism, direct activation of Bax by p53 becomes critical to IR-induced-damage initiation.In contrast, the combined inhibition of Bid and Bax elicits an anti-apoptotic response that is effective over a range of time delays.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Computational &Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2].

ABSTRACT
Developing pharmacological strategies for controlling ionizing radiation (IR)-induced cell death is important for both mitigating radiation damage and alleviating the side effects of anti-cancer radiotherapy manifested in surrounding tissue morbidity. Exposure to IR often triggers the onset of p53-dependent apoptotic pathways. Here we build a stochastic model of p53 induced apoptosis comprised of coupled modules of nuclear p53 activation, mitochondrial cytochrome c release and cytosolic caspase activation that also takes into account cellular heterogeneity. Our simulations show that the strength of p53 transcriptional activity and its coupling (or timing with respect) to mitochondrial pore opening are major determinants of cell fate: for systems where apoptosis is elicited via a p53-transcription-independent mechanism, direct activation of Bax by p53 becomes critical to IR-induced-damage initiation. We further show that immediate administration of PUMA inhibitors following IR exposure effectively suppresses excessive cell death, provided that there is a strong caspase/Bid feedback loop; however, the efficacy of the treatment diminishes with increasing delay in treatment implementation. In contrast, the combined inhibition of Bid and Bax elicits an anti-apoptotic response that is effective over a range of time delays.

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Related in: MedlinePlus

Simulation of p53 and Mdm2 dynamics.(A) Comparison of stochastic (left) and deterministic (right) simulations. The time profiles of p53(N) and Mdm2(N) were simulated using the stochastic approach (leftpanel) and a deterministic approach with the same kinetic parameters (right panel). The stochastic simulation shows sustained oscillations while the deterministic simulation results in damped oscillations. (B) Radiation exposure is initiated at t = 0 (upon alteration of kinetic parameters, which applies for a duration of 12 h (left) or 56 h (right)), and leads to p53 oscillations. The amount of the radiation doses for 12 h and 56 h cases are comparable to 10 seconds and 5.6 min γ-irradiation (60Co, 1.8 Gy min−1) treatments, respectively7.
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f2: Simulation of p53 and Mdm2 dynamics.(A) Comparison of stochastic (left) and deterministic (right) simulations. The time profiles of p53(N) and Mdm2(N) were simulated using the stochastic approach (leftpanel) and a deterministic approach with the same kinetic parameters (right panel). The stochastic simulation shows sustained oscillations while the deterministic simulation results in damped oscillations. (B) Radiation exposure is initiated at t = 0 (upon alteration of kinetic parameters, which applies for a duration of 12 h (left) or 56 h (right)), and leads to p53 oscillations. The amount of the radiation doses for 12 h and 56 h cases are comparable to 10 seconds and 5.6 min γ-irradiation (60Co, 1.8 Gy min−1) treatments, respectively7.

Mentions: We adopted stochastic simulations for two reasons. First, the quantity of some proteins such as caspase-3 are expected to be extremely low (or non-existent) under homeostatic conditions. Second, as Figure 2A shows, stochastic simulations reproduce the sustained oscillations of p53(N) and Mdm2(N) in accord with experiments6741, while deterministic simulations result in damped oscillations.


Significance of p53 dynamics in regulating apoptosis in response to ionizing radiation, and polypharmacological strategies.

Liu B, Bhatt D, Oltvai ZN, Greenberger JS, Bahar I - Sci Rep (2014)

Simulation of p53 and Mdm2 dynamics.(A) Comparison of stochastic (left) and deterministic (right) simulations. The time profiles of p53(N) and Mdm2(N) were simulated using the stochastic approach (leftpanel) and a deterministic approach with the same kinetic parameters (right panel). The stochastic simulation shows sustained oscillations while the deterministic simulation results in damped oscillations. (B) Radiation exposure is initiated at t = 0 (upon alteration of kinetic parameters, which applies for a duration of 12 h (left) or 56 h (right)), and leads to p53 oscillations. The amount of the radiation doses for 12 h and 56 h cases are comparable to 10 seconds and 5.6 min γ-irradiation (60Co, 1.8 Gy min−1) treatments, respectively7.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150106&req=5

f2: Simulation of p53 and Mdm2 dynamics.(A) Comparison of stochastic (left) and deterministic (right) simulations. The time profiles of p53(N) and Mdm2(N) were simulated using the stochastic approach (leftpanel) and a deterministic approach with the same kinetic parameters (right panel). The stochastic simulation shows sustained oscillations while the deterministic simulation results in damped oscillations. (B) Radiation exposure is initiated at t = 0 (upon alteration of kinetic parameters, which applies for a duration of 12 h (left) or 56 h (right)), and leads to p53 oscillations. The amount of the radiation doses for 12 h and 56 h cases are comparable to 10 seconds and 5.6 min γ-irradiation (60Co, 1.8 Gy min−1) treatments, respectively7.
Mentions: We adopted stochastic simulations for two reasons. First, the quantity of some proteins such as caspase-3 are expected to be extremely low (or non-existent) under homeostatic conditions. Second, as Figure 2A shows, stochastic simulations reproduce the sustained oscillations of p53(N) and Mdm2(N) in accord with experiments6741, while deterministic simulations result in damped oscillations.

Bottom Line: Here we build a stochastic model of p53 induced apoptosis comprised of coupled modules of nuclear p53 activation, mitochondrial cytochrome c release and cytosolic caspase activation that also takes into account cellular heterogeneity.Our simulations show that the strength of p53 transcriptional activity and its coupling (or timing with respect) to mitochondrial pore opening are major determinants of cell fate: for systems where apoptosis is elicited via a p53-transcription-independent mechanism, direct activation of Bax by p53 becomes critical to IR-induced-damage initiation.In contrast, the combined inhibition of Bid and Bax elicits an anti-apoptotic response that is effective over a range of time delays.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Computational &Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2].

ABSTRACT
Developing pharmacological strategies for controlling ionizing radiation (IR)-induced cell death is important for both mitigating radiation damage and alleviating the side effects of anti-cancer radiotherapy manifested in surrounding tissue morbidity. Exposure to IR often triggers the onset of p53-dependent apoptotic pathways. Here we build a stochastic model of p53 induced apoptosis comprised of coupled modules of nuclear p53 activation, mitochondrial cytochrome c release and cytosolic caspase activation that also takes into account cellular heterogeneity. Our simulations show that the strength of p53 transcriptional activity and its coupling (or timing with respect) to mitochondrial pore opening are major determinants of cell fate: for systems where apoptosis is elicited via a p53-transcription-independent mechanism, direct activation of Bax by p53 becomes critical to IR-induced-damage initiation. We further show that immediate administration of PUMA inhibitors following IR exposure effectively suppresses excessive cell death, provided that there is a strong caspase/Bid feedback loop; however, the efficacy of the treatment diminishes with increasing delay in treatment implementation. In contrast, the combined inhibition of Bid and Bax elicits an anti-apoptotic response that is effective over a range of time delays.

Show MeSH
Related in: MedlinePlus