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

DEMİRKIRAN G., KALAYCI DEMİR G., Guzelis C.

IET SYSTEMS BIOLOGY, cilt.12, sa.1, ss.26-38, 2018 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 12 Sayı: 1
  • Basım Tarihi: 2018
  • Doi Numarası: 10.1049/iet-syb.2017.0041
  • Dergi Adı: IET SYSTEMS BIOLOGY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.26-38
  • Anahtar Kelimeler: physiological models, cellular biophysics, cancer, difference equations, delays, enzymes, biochemistry, molecular biophysics, gamma-rays, radiation therapy, two-phase dynamics model, P53 network, gamma irradiation, 2D relaxation oscillator model, ATM model, Wip1 variables, p53-regulators, cell fate decision, excitable relaxation oscillator, Wip1 time delay, state-dependent delay differential equation, cell cycle arrest, cell apoptosis, cancer therapies, Wip1 overexpression, Wip1 downregulation, ATM deficiency, Mdm2 overexpression, Mdm2 downregulation, mutation effects, phase space approach, WIP1 PHOSPHATASE, BREAST-CANCER, CELL-CYCLE, DOWN-REGULATION, PPM1D, ATM, AMPLIFICATION, ACTIVATION, RADIATION, APOPTOSIS
  • Dokuz Eylül Üniversitesi Adresli: Evet

Özet

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.