title: Significance of p53 dynamics in regulating apoptosis in response to ionizing radiation, and polypharmacological strategies.
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.
authors.affiliation: 1] Department of Computational &Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2].
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: 1] Department of Computational &Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2].
authors.forename: Divesh
authors.initials: D
authors.lastname: Bhatt
authors.affiliation: 1] Department of Computational &Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA [2] Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Zoltán N
authors.initials: ZN
authors.lastname: Oltvai
authors.affiliation: Department of Radiation Oncology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Joel S
authors.initials: JS
authors.lastname: Greenberger
authors.affiliation: Department of Computational &Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
mesh_terms: D017209:Apoptosis / Q000502:physiology* / Q000528:radiation effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology / Q000528:radiation effects; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects; D004789:Enzyme Activation / Q000502:physiology / Q000528:radiation effects; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects; D015233:Models, Statistical; D011839:Radiation, Ionizing; D014158:Transcription, Genetic / Q000502:physiology / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D020169:Caspases