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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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Simulated apoptotic response with different strengths of coupling between p53 dynamics and mitochondrial events.(A) Caspase-3 time profile for different rates of p53 transcriptional activation of pro-apoptotic proteins (represented by k11). (B) Caspase-3 time profile for different p53 translocation rate from the cytoplasm to the mitochondria (represented by k10). (C) The simulated coupling strength-caspase activation response curves. (D) Caspase-3 time profile under low frequency (of p53 pulses) conditions. This condition is denoted as LF, while normal frequency conditions are denoted as WT. The associated parameters can be found in Supplementary Table S3.
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f4: Simulated apoptotic response with different strengths of coupling between p53 dynamics and mitochondrial events.(A) Caspase-3 time profile for different rates of p53 transcriptional activation of pro-apoptotic proteins (represented by k11). (B) Caspase-3 time profile for different p53 translocation rate from the cytoplasm to the mitochondria (represented by k10). (C) The simulated coupling strength-caspase activation response curves. (D) Caspase-3 time profile under low frequency (of p53 pulses) conditions. This condition is denoted as LF, while normal frequency conditions are denoted as WT. The associated parameters can be found in Supplementary Table S3.

Mentions: p53A and p53(M) initiate the p53-transcription-dependent and -independent apoptotic events, respectively, by either upregulating pro-apoptotic proteins (represented by PUMA and Bax), or interacting with antiapoptotic Bcl-2 family proteins. These may lead to MOMP opening, cyt c release and caspase activation depending on the coupling between the two pathways, which in turn depend on the relative rates of (i) transcriptional activation of pro-apoptotic proteins by p53(N) (k11) and (ii) translocation of p53(C) to the mitochondria (k10). We varied k11 and k10, and simulated the time profiles of caspase-3 activation (commonly used as an indicator of apoptosis) toward elucidating the relative sensitivity of caspase-3 activation to these two p53-mediated mechanisms - higher k11 and k10 values representing the dominance of transcription-dependent and -independent activities of p53, respectively. The results are presented in Figure 4A and 4B.


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)

Simulated apoptotic response with different strengths of coupling between p53 dynamics and mitochondrial events.(A) Caspase-3 time profile for different rates of p53 transcriptional activation of pro-apoptotic proteins (represented by k11). (B) Caspase-3 time profile for different p53 translocation rate from the cytoplasm to the mitochondria (represented by k10). (C) The simulated coupling strength-caspase activation response curves. (D) Caspase-3 time profile under low frequency (of p53 pulses) conditions. This condition is denoted as LF, while normal frequency conditions are denoted as WT. The associated parameters can be found in Supplementary Table S3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Simulated apoptotic response with different strengths of coupling between p53 dynamics and mitochondrial events.(A) Caspase-3 time profile for different rates of p53 transcriptional activation of pro-apoptotic proteins (represented by k11). (B) Caspase-3 time profile for different p53 translocation rate from the cytoplasm to the mitochondria (represented by k10). (C) The simulated coupling strength-caspase activation response curves. (D) Caspase-3 time profile under low frequency (of p53 pulses) conditions. This condition is denoted as LF, while normal frequency conditions are denoted as WT. The associated parameters can be found in Supplementary Table S3.
Mentions: p53A and p53(M) initiate the p53-transcription-dependent and -independent apoptotic events, respectively, by either upregulating pro-apoptotic proteins (represented by PUMA and Bax), or interacting with antiapoptotic Bcl-2 family proteins. These may lead to MOMP opening, cyt c release and caspase activation depending on the coupling between the two pathways, which in turn depend on the relative rates of (i) transcriptional activation of pro-apoptotic proteins by p53(N) (k11) and (ii) translocation of p53(C) to the mitochondria (k10). We varied k11 and k10, and simulated the time profiles of caspase-3 activation (commonly used as an indicator of apoptosis) toward elucidating the relative sensitivity of caspase-3 activation to these two p53-mediated mechanisms - higher k11 and k10 values representing the dominance of transcription-dependent and -independent activities of p53, respectively. The results are presented in Figure 4A and 4B.

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