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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

Model predictions and validation.The time profiles of p53(N) and Mdm2(N) (A), the histograms of the period (B) and amplitude (C) of oscillations for Mdm2(N) under IR are simulated and compared against previous experimental observations. Blue solid lines and bars depict the simulation results and red dots and bars indicate experimental data. The data in blue lines and red dots were normalized so that their maximum value was equal to 1. The experimental data in (A), (B) and (C) were extracted from Lahav et al, 200441, Geva-Zatorsky et al, 20067 and Geva-Zatorsky et al, 201042, respectively. (D) The dynamical properties predicted by the model are supported by experimental evidence7124144454647 (type I error = 0.05, type II error = 0.05, see further details in Supplementary Material).
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f3: Model predictions and validation.The time profiles of p53(N) and Mdm2(N) (A), the histograms of the period (B) and amplitude (C) of oscillations for Mdm2(N) under IR are simulated and compared against previous experimental observations. Blue solid lines and bars depict the simulation results and red dots and bars indicate experimental data. The data in blue lines and red dots were normalized so that their maximum value was equal to 1. The experimental data in (A), (B) and (C) were extracted from Lahav et al, 200441, Geva-Zatorsky et al, 20067 and Geva-Zatorsky et al, 201042, respectively. (D) The dynamical properties predicted by the model are supported by experimental evidence7124144454647 (type I error = 0.05, type II error = 0.05, see further details in Supplementary Material).

Mentions: Figure 3A shows the comparison of the model-predicted time profiles of p53(N) and Mdm2(N) (blue lines) with time series western blot data41 (red dots). 1,000 stochastic trajectories were generated (under the same initial conditions but with different random seeds) and averaged to mimic the heterogeneous cell population behavior. Good agreement is achieved between predicted time profiles and experimental data.


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)

Model predictions and validation.The time profiles of p53(N) and Mdm2(N) (A), the histograms of the period (B) and amplitude (C) of oscillations for Mdm2(N) under IR are simulated and compared against previous experimental observations. Blue solid lines and bars depict the simulation results and red dots and bars indicate experimental data. The data in blue lines and red dots were normalized so that their maximum value was equal to 1. The experimental data in (A), (B) and (C) were extracted from Lahav et al, 200441, Geva-Zatorsky et al, 20067 and Geva-Zatorsky et al, 201042, respectively. (D) The dynamical properties predicted by the model are supported by experimental evidence7124144454647 (type I error = 0.05, type II error = 0.05, see further details in Supplementary Material).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f3: Model predictions and validation.The time profiles of p53(N) and Mdm2(N) (A), the histograms of the period (B) and amplitude (C) of oscillations for Mdm2(N) under IR are simulated and compared against previous experimental observations. Blue solid lines and bars depict the simulation results and red dots and bars indicate experimental data. The data in blue lines and red dots were normalized so that their maximum value was equal to 1. The experimental data in (A), (B) and (C) were extracted from Lahav et al, 200441, Geva-Zatorsky et al, 20067 and Geva-Zatorsky et al, 201042, respectively. (D) The dynamical properties predicted by the model are supported by experimental evidence7124144454647 (type I error = 0.05, type II error = 0.05, see further details in Supplementary Material).
Mentions: Figure 3A shows the comparison of the model-predicted time profiles of p53(N) and Mdm2(N) (blue lines) with time series western blot data41 (red dots). 1,000 stochastic trajectories were generated (under the same initial conditions but with different random seeds) and averaged to mimic the heterogeneous cell population behavior. Good agreement is achieved between predicted time profiles and experimental data.

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