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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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Role of tBid activation for sustained caspase-3 activity and effect of the strength of caspase/Bid positive feedback loop in mediating apoptosis and its inhibition.(A–B) Time evolution of the concentrations of PUMA, caspase-3, and tBid at in response to long time IR exposure predicted for two different coupling strengths of p53 transcriptional activation to mitochondrial pore opening events (represented by k11). PUMA exhibits oscillations echoing the behavior of p53. tBid production remains limited (red curve) on the left panel A (low k11) such that caspase-3 levels are negligibly small. Enhanced coupling (right panel) yields a sustained increase in tBid levels, which in turn induces a significant increase in caspase-3 levels, via a positive feedback loop. Note the ordinate scale difference between the two panels. (C) The caspase-3 time profiles were simulated for three k28, which correspond to different strengths of caspase/Bid feedback loop. Upon decreasing k28, caspase-3 concentration progressively decreases. (D) Feedback loop strength-caspase activation response curves.
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f6: Role of tBid activation for sustained caspase-3 activity and effect of the strength of caspase/Bid positive feedback loop in mediating apoptosis and its inhibition.(A–B) Time evolution of the concentrations of PUMA, caspase-3, and tBid at in response to long time IR exposure predicted for two different coupling strengths of p53 transcriptional activation to mitochondrial pore opening events (represented by k11). PUMA exhibits oscillations echoing the behavior of p53. tBid production remains limited (red curve) on the left panel A (low k11) such that caspase-3 levels are negligibly small. Enhanced coupling (right panel) yields a sustained increase in tBid levels, which in turn induces a significant increase in caspase-3 levels, via a positive feedback loop. Note the ordinate scale difference between the two panels. (C) The caspase-3 time profiles were simulated for three k28, which correspond to different strengths of caspase/Bid feedback loop. Upon decreasing k28, caspase-3 concentration progressively decreases. (D) Feedback loop strength-caspase activation response curves.

Mentions: Figure 6 displays the time evolution of PUMA, tBid(M) and caspase-3, after exposure to IR. PUMA (black) mirrors the p53 oscillations, presumably due to its direct transcriptional regulation by p53. Interestingly, PUMA levels decay after termination of IR exposure, but there is sustained tBid fluctuations and newly elicited caspase-3 production even after the decay of PUMA. Sustained activation becomes more prominent with increasing coupling to p53 transcriptional machinery (high k11, Figure 6B). Caspase-3 activation depends on whether sufficient tBid is activated by the time PUMA decays. The increase in [tBid] (and associated positive feedback to Bax) is critically important for sustained caspase activity. Otherwise, PUMA and Bax upregulation may fall short of triggering efficient cyt c release. Under these circumstances, the extent of Bax activation by p53(M) (k10, k29) or PUMA (k30) may become critical.


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)

Role of tBid activation for sustained caspase-3 activity and effect of the strength of caspase/Bid positive feedback loop in mediating apoptosis and its inhibition.(A–B) Time evolution of the concentrations of PUMA, caspase-3, and tBid at in response to long time IR exposure predicted for two different coupling strengths of p53 transcriptional activation to mitochondrial pore opening events (represented by k11). PUMA exhibits oscillations echoing the behavior of p53. tBid production remains limited (red curve) on the left panel A (low k11) such that caspase-3 levels are negligibly small. Enhanced coupling (right panel) yields a sustained increase in tBid levels, which in turn induces a significant increase in caspase-3 levels, via a positive feedback loop. Note the ordinate scale difference between the two panels. (C) The caspase-3 time profiles were simulated for three k28, which correspond to different strengths of caspase/Bid feedback loop. Upon decreasing k28, caspase-3 concentration progressively decreases. (D) Feedback loop strength-caspase activation response curves.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f6: Role of tBid activation for sustained caspase-3 activity and effect of the strength of caspase/Bid positive feedback loop in mediating apoptosis and its inhibition.(A–B) Time evolution of the concentrations of PUMA, caspase-3, and tBid at in response to long time IR exposure predicted for two different coupling strengths of p53 transcriptional activation to mitochondrial pore opening events (represented by k11). PUMA exhibits oscillations echoing the behavior of p53. tBid production remains limited (red curve) on the left panel A (low k11) such that caspase-3 levels are negligibly small. Enhanced coupling (right panel) yields a sustained increase in tBid levels, which in turn induces a significant increase in caspase-3 levels, via a positive feedback loop. Note the ordinate scale difference between the two panels. (C) The caspase-3 time profiles were simulated for three k28, which correspond to different strengths of caspase/Bid feedback loop. Upon decreasing k28, caspase-3 concentration progressively decreases. (D) Feedback loop strength-caspase activation response curves.
Mentions: Figure 6 displays the time evolution of PUMA, tBid(M) and caspase-3, after exposure to IR. PUMA (black) mirrors the p53 oscillations, presumably due to its direct transcriptional regulation by p53. Interestingly, PUMA levels decay after termination of IR exposure, but there is sustained tBid fluctuations and newly elicited caspase-3 production even after the decay of PUMA. Sustained activation becomes more prominent with increasing coupling to p53 transcriptional machinery (high k11, Figure 6B). Caspase-3 activation depends on whether sufficient tBid is activated by the time PUMA decays. The increase in [tBid] (and associated positive feedback to Bax) is critically important for sustained caspase activity. Otherwise, PUMA and Bax upregulation may fall short of triggering efficient cyt c release. Under these circumstances, the extent of Bax activation by p53(M) (k10, k29) or PUMA (k30) may become critical.

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