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Mathematical modelling of core regulatory mechanism in p53 protein that activates apoptotic switch

Ket Hing Chong1, Sandhya Samarasinghe2, Don Kulasiri3

  • 1Biomedical Informatics Lab, School of Computer Science and Engineering, Nanyang Technological University, 639798, Singapore.

Journal of Theoretical Biology
|November 16, 2018
PubMed

Insights

The p53 protein, a tumor suppressor, triggers apoptosis via an all-or-none switch in response to DNA damage. This study models how ATM auto-activation regulates this p53-mediated apoptotic switch, identifying Bcl2 overexpression as a potential malfunction factor.

Area of Science:

  • Cellular biology
  • Systems biology
  • Biophysics

Background:

  • The p53 protein is a critical tumor suppressor involved in DNA damage response, activating apoptosis through the intrinsic pathway.
  • Apoptosis, or programmed cell death, has been observed to occur in an all-or-none, switch-like manner in response to cellular stress.
  • Understanding the precise molecular mechanisms governing p53-mediated apoptosis is crucial for comprehending cell fate decisions.

Purpose of the Study:

  • To investigate the regulatory design principles governing p53 activation of the apoptotic switch.
  • To develop a mathematical model of p53's role in apoptosis initiation following sustained DNA double-strand breaks.
  • To identify the specific molecular components responsible for threshold activation of apoptosis.

Main Methods:

  • Developed a mathematical model integrating p53 core regulation and apoptosis initiation modules (Puma, Bcl2, Bax).
  • Incorporated ATM (ataxia-telangiectasia mutated) auto-activation, hypothesizing its role in threshold control based on damage intensity.
  • Simulated molecular interactions within the p53 network to analyze cell fate determination.

Main Results:

  • The model successfully reproduced the experimentally observed all-or-none apoptosis activation.
  • Simulation results indicated that ATM auto-activation, dependent on damage intensity, controls the p53 apoptotic threshold.
  • Overexpression of Bcl2 was predicted as a factor that could lead to apoptotic switch malfunction.

Conclusions:

  • A simplified yet plausible model elucidates the molecular mechanisms controlling p53-mediated apoptosis.
  • ATM auto-activation plays a key role in setting the threshold for p53-dependent apoptosis.
  • The study highlights the importance of precise molecular regulation for proper cell fate decisions and identifies potential causes of apoptosis dysregulation.
Keywords:
ApoptosisApoptotic switchDNA Damage responseMathematical modellingp53

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