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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

Robustness of caspase-3 activity with respect to association strength of Bax(M) and Bcl-2 in the mitochondria.Panels A and C show onset of apoptosis (blue curve, for C3; right ordinate) despite vastly differing dissociation constants, k25−/k25+, for the Bax(M).Bcl-2 complex formed in the mitochondria (k11 = 2 × 10−5 s−1 in these two panels). Note the different scales for the [Bax(M).Bcl-2] profiles in panels A and C (black curve; left ordinate). Likewise, panels B and D show the insensitivity of the system behavior (low C3 levels) to k25−/k25+, under conditions conducive to cell survival (k11 = 10−5 s−1).
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f5: Robustness of caspase-3 activity with respect to association strength of Bax(M) and Bcl-2 in the mitochondria.Panels A and C show onset of apoptosis (blue curve, for C3; right ordinate) despite vastly differing dissociation constants, k25−/k25+, for the Bax(M).Bcl-2 complex formed in the mitochondria (k11 = 2 × 10−5 s−1 in these two panels). Note the different scales for the [Bax(M).Bcl-2] profiles in panels A and C (black curve; left ordinate). Likewise, panels B and D show the insensitivity of the system behavior (low C3 levels) to k25−/k25+, under conditions conducive to cell survival (k11 = 10−5 s−1).

Mentions: k25−/k25+ widely varies with experimental conditions and cell type2627. Values spanning several orders of magnitude, from micromolar to nanomolar, have been reported for this dissociation constant by different groups (see the Supplementary Text). Figure 5 shows caspase-3 and Bax(M).Bcl-2 complex concentrations for two different k25−/k25+ values. Comparison of Figure 5A and C shows that the caspase-3 levels (blue curve, right ordinate) are unaffected by variation in the dissociation constants over two orders of magnitude. In contrast, vastly differing amounts of Bax(M). Bcl-2 complex may be formed (black curve, left ordinate) consistent with the change in the dissociation constant. Similarly, the different dissociation constants had an insignificant effect under anti-apoptotic conditions (panels 5B and D).


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)

Robustness of caspase-3 activity with respect to association strength of Bax(M) and Bcl-2 in the mitochondria.Panels A and C show onset of apoptosis (blue curve, for C3; right ordinate) despite vastly differing dissociation constants, k25−/k25+, for the Bax(M).Bcl-2 complex formed in the mitochondria (k11 = 2 × 10−5 s−1 in these two panels). Note the different scales for the [Bax(M).Bcl-2] profiles in panels A and C (black curve; left ordinate). Likewise, panels B and D show the insensitivity of the system behavior (low C3 levels) to k25−/k25+, under conditions conducive to cell survival (k11 = 10−5 s−1).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5: Robustness of caspase-3 activity with respect to association strength of Bax(M) and Bcl-2 in the mitochondria.Panels A and C show onset of apoptosis (blue curve, for C3; right ordinate) despite vastly differing dissociation constants, k25−/k25+, for the Bax(M).Bcl-2 complex formed in the mitochondria (k11 = 2 × 10−5 s−1 in these two panels). Note the different scales for the [Bax(M).Bcl-2] profiles in panels A and C (black curve; left ordinate). Likewise, panels B and D show the insensitivity of the system behavior (low C3 levels) to k25−/k25+, under conditions conducive to cell survival (k11 = 10−5 s−1).
Mentions: k25−/k25+ widely varies with experimental conditions and cell type2627. Values spanning several orders of magnitude, from micromolar to nanomolar, have been reported for this dissociation constant by different groups (see the Supplementary Text). Figure 5 shows caspase-3 and Bax(M).Bcl-2 complex concentrations for two different k25−/k25+ values. Comparison of Figure 5A and C shows that the caspase-3 levels (blue curve, right ordinate) are unaffected by variation in the dissociation constants over two orders of magnitude. In contrast, vastly differing amounts of Bax(M). Bcl-2 complex may be formed (black curve, left ordinate) consistent with the change in the dissociation constant. Similarly, the different dissociation constants had an insignificant effect under anti-apoptotic conditions (panels 5B and D).

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