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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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Simplified reaction network diagram of the mathematical model.The diagram highlights the major reactions in the model. Basal protein synthesis and degradation reactions are included in the model but not shown. The full list of components, reactions and kinetic equations, and parameters are presented in the Supplementary Tables S1 and S2. Complexes are denoted by the names of their components, separated by a dot. Single-headed solid arrows characterize irreversible reactions and double-headed arrows, reversible reactions. Dotted arrows represent enzymatic reactions. The reactions computed by sensitivity analysis (Supplementary Figure S2) to play a significant role are shown by red arrows. Among them, the kinetic steps 20 and 10 (or associated rate constants k20 and k10) lead to the respective transcription-dependent and -independent activities of p53.
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f1: Simplified reaction network diagram of the mathematical model.The diagram highlights the major reactions in the model. Basal protein synthesis and degradation reactions are included in the model but not shown. The full list of components, reactions and kinetic equations, and parameters are presented in the Supplementary Tables S1 and S2. Complexes are denoted by the names of their components, separated by a dot. Single-headed solid arrows characterize irreversible reactions and double-headed arrows, reversible reactions. Dotted arrows represent enzymatic reactions. The reactions computed by sensitivity analysis (Supplementary Figure S2) to play a significant role are shown by red arrows. Among them, the kinetic steps 20 and 10 (or associated rate constants k20 and k10) lead to the respective transcription-dependent and -independent activities of p53.

Mentions: We first constructed a mathematical model for the biochemical network associated with IR-induced apoptosis. Our model consists of three closely interconnected subnets (Figure 1): an upstream p53 module, a mitochondrial module and caspase activation events triggered upon mitochondrial cytochrome c (cyt c) release. The interactions are distributed across three subcellular locations: nucleus (N), cytosol (C) and mitochondria (M), indicated by superscripts.


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)

Simplified reaction network diagram of the mathematical model.The diagram highlights the major reactions in the model. Basal protein synthesis and degradation reactions are included in the model but not shown. The full list of components, reactions and kinetic equations, and parameters are presented in the Supplementary Tables S1 and S2. Complexes are denoted by the names of their components, separated by a dot. Single-headed solid arrows characterize irreversible reactions and double-headed arrows, reversible reactions. Dotted arrows represent enzymatic reactions. The reactions computed by sensitivity analysis (Supplementary Figure S2) to play a significant role are shown by red arrows. Among them, the kinetic steps 20 and 10 (or associated rate constants k20 and k10) lead to the respective transcription-dependent and -independent activities of p53.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Simplified reaction network diagram of the mathematical model.The diagram highlights the major reactions in the model. Basal protein synthesis and degradation reactions are included in the model but not shown. The full list of components, reactions and kinetic equations, and parameters are presented in the Supplementary Tables S1 and S2. Complexes are denoted by the names of their components, separated by a dot. Single-headed solid arrows characterize irreversible reactions and double-headed arrows, reversible reactions. Dotted arrows represent enzymatic reactions. The reactions computed by sensitivity analysis (Supplementary Figure S2) to play a significant role are shown by red arrows. Among them, the kinetic steps 20 and 10 (or associated rate constants k20 and k10) lead to the respective transcription-dependent and -independent activities of p53.
Mentions: We first constructed a mathematical model for the biochemical network associated with IR-induced apoptosis. Our model consists of three closely interconnected subnets (Figure 1): an upstream p53 module, a mitochondrial module and caspase activation events triggered upon mitochondrial cytochrome c (cyt c) release. The interactions are distributed across three subcellular locations: nucleus (N), cytosol (C) and mitochondria (M), indicated by superscripts.

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