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access icon openaccess Revealing determinants of two-phase dynamics of P53 network under gamma irradiation based on a reduced 2D relaxation oscillator model

This is an open access article published by the IET under the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/)
Received 24/07/2017, Accepted 25/10/2017, Revised 17/10/2017, Published 08/11/2017

This 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.

Inspec keywords: cancer; molecular biophysics; cellular biophysics; biochemistry; difference equations; delays; gamma-rays; physiological models; radiation therapy; enzymes

Other keywords: Mdm2 downregulation; P53 network; cell cycle arrest; Wip1 variables; p53-regulators; cell fate decision; 2D relaxation oscillator model; gamma irradiation; Mdm2 overexpression; state-dependent delay differential equation; Wip1 overexpression; phase space approach; excitable relaxation oscillator; Wip1 downregulation; cancer therapies; mutation effects; ATM deficiency; two-phase dynamics model; Wip1 time delay; cell apoptosis; ATM model

Subjects: Physical chemistry of biomolecular solutions and condensed states; Cellular biophysics; Radiation therapy; Biomolecular structure, configuration, conformation, and active sites; Biomolecular dynamics, molecular probes, molecular pattern recognition; Interactions with radiations at the biomolecular level

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