Gökhan DemirkıranGüleser Kalayci DemirCüneyt GüzelişGuzelis, CuneytDemirkiran, GokhanDemir, Guleser Kalayci2025-10-06201817518849, 175188571751-88491751-885710.1049/iet-syb.2017.00412-s2.0-85040778587https://www.scopus.com/inward/record.uri?eid=2-s2.0-85040778587&doi=10.1049%2Fiet-syb.2017.0041&partnerID=40&md5=0b76f612b5270f668d5a8ca5c6f839b3https://gcris.yasar.edu.tr/handle/123456789/9581https://doi.org/10.1049/iet-syb.2017.0041This study proposes a two-dimensional (2D) oscillator model of p53 network which is derived via reducing the multidimensional two-phase dynamics model into a model of ataxia telangiectasia mutated (ATM) and Wip1 variables and studies the impact of p53-regulators on cell fate decision. First the authors identify a 6D core oscillator module then reduce this module into a 2D oscillator model while preserving the qualitative behaviours. The introduced 2D model is shown to be an excitable relaxation oscillator. This oscillator provides a mechanism that leads diverse modes underpinning cell fate each corresponding to a cell state. To investigate the effects of p53 inhibitors and the intrinsic time delay of Wip1 on the characteristics of oscillations they introduce also a delay differential equation version of the 2D oscillator. They observe that the suppression of p53 inhibitors decreases the amplitudes of p53 oscillation though the suppression increases the sustained level of p53. They identify Wip1 and P53DINP1 as possible targets for cancer therapies considering their impact on the oscillator supported by biological findings. They model some mutations as critical changes of the phase space characteristics. Possible cancer therapeutic strategies are then proposed for preventing these mutations' effects using the phase space approach. © 2018 Elsevier B.V. All rights reserved.Englishinfo:eu-repo/semantics/openAccessCarrier Protein, Phosphoprotein Phosphatase, Protein Phosphatase 2c, Ataxia Telangiectasia Mutated Proteins, Carrier Proteins, Heat-shock Proteins, Ppm1d Protein Human, Protein Phosphatase 2c, Tp53inp1 Protein Human, Tumor Suppressor Protein P53, Differential Equations, Diseases, Irradiation, Phase Space Methods, Ataxia-telangiectasia Mutated, Cell Fate Decision, Delay Differential Equations, Gamma Irradiation, Oscillator Model, Oscillator Module, Therapeutic Strategy, Two Dimensional (2 D), Relaxation Oscillators, Atm Protein, Carrier Protein, Heat Shock Protein, Ppm1d Protein Human, Protein P53, Protein Phosphatase 2c, Tp53inp1 Protein Human, Gamma Radiation, Metabolism, Neoplasm, Physiology, Theoretical Model, Ataxia Telangiectasia Mutated Proteins, Carrier Proteins, Gamma Rays, Heat-shock Proteins, Models Theoretical, Neoplasms, Protein Phosphatase 2c, Tumor Suppressor Protein P53Differential equations, Diseases, Irradiation, Phase space methods, Ataxia-telangiectasia mutated, Cell fate decision, Delay differential equations, Gamma irradiation, Oscillator model, Oscillator module, Therapeutic strategy, Two Dimensional (2 D), Relaxation oscillators, ATM protein, carrier protein, heat shock protein, PPM1D protein human, protein p53, protein phosphatase 2c, TP53INP1 protein human, gamma radiation, metabolism, neoplasm, physiology, theoretical model, Ataxia Telangiectasia Mutated Proteins, Carrier Proteins, Gamma Rays, Heat-Shock Proteins, Models Theoretical, Neoplasms, Protein Phosphatase 2C, Tumor Suppressor Protein p53Mdm2 DownregulationCellular Biophysics2D Relaxation Oscillator ModelEnzymesCell Cycle ArrestDifference EquationsATM DeficiencyPhysiological ModelsState-Dependent Delay Differential EquationExcitable Relaxation OscillatorCancer TherapiesMutation EffectsWip1 DownregulationWip1 Time DelayTwo-Phase Dynamics ModelMdm2 OverexpressionATM ModelP53-regulatorsPhase Space ApproachWip1 VariablesWip1 OverexpressionCell Fate DecisionDelaysBiochemistryRadiation TherapyP53 NetworkGamma IrradiationGamma-raysCell ApoptosisCancerMolecular BiophysicsArticle