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Significance of p53 dynamics in regulating apoptosis in response to ionizing radiation, and polypharmacological strategies

Bing Liu, Divesh Bhatt, Zoltán N. Oltvai and Ivet Bahar

 
Reaction network diagram of the p53-medaited apoptosis pathway model.

Reaction network diagram of the p53-medaited apoptosis pathway model.

Understanding the mechanism of cellular response to ionizing radiation (IR) damage is important from the perspectives of both radiotherapy and mitigation of radiation damage. Cell response to IR involves several protein-DNA and protein-protein interactions, as well as the formation of free radicals that alter cellular biochemistry. Cell death, mediated by the tumor suppressor protein p53, usually takes place several hours after radiation injury. Even if the exposure to radiation is brief, its effect on cellular biochemistry may be long-lived depending on the strength of IR. The responses to treatments that aim at alleviating radiation damage (or decreasing the susceptibility to apoptosis in damaged cells) depend on the dosage and duration of exposure, the treatment timing, and the dynamics of the proteins that regulate apoptotic events.

In a recent work, we employed systems biology approaches to study the dynamics of p53 signaling network in response to IR, as well as the pharmacological strategies for controlling ionizing radiation (IR)-induced cell death. We constructed and calibrated a stochastic model of the p53 network comprised of coupled modules of nuclear p53 activation, mitochondrial cytochrome c release and cytosolic caspase activation. The model takes into account cellular heterogeneity and is able to reproduce previously published experimental observations.

Recent studies suggested that different p53 dynamics (repeated pulses vs sustained response) may alter cell fate. Our model analysis showed that the p53 oscillatory behavior in response to IR is not, per se, sufficient to explain a cell's susceptibility to apoptosis; rather, the dynamic coupling between the p53 module and mitochondrial machinery is important. Among transcription-dependent and -independent roles of p53, the former plays a major role in driving apoptosis via transcriptional activation of Bax. Our study also shed light to the strength of caspase/tBid feedback loop as a determinant of apoptotic response as well as treatment efficacy. Specifically, when the feedback is sufficiently strong, inhibition of pro-apoptotic proteins like PUMA mitigates damage; but the effect weakens with delay in inhibitor administration. Further, we show that the combined inhibition of Bid and Bax elicits an anti-apoptotic response that is effective over a range of time delays.

Our results highlighted the significance of the timing between genotoxic stress and therapeutic intervention in the context of the cell stochastics. They also offered new insights into novel polypharmacological strategies for alleviating IR damage as well as controlling cell susceptibility to apoptosis under other disease states and environmental challenges.

Related publication: Liu B, Bhatt D, Oltvai ZN, Greenberger JS, Bahar I (2014) Significance of p53 dynamics in regulating apoptosis in response to ionizing radiation, and polypharmacological strategies Sci Rep 4: 6245

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