Stochasticity of Intranuclear Biochemical Reaction Processes Controls the Final Decision of Cell Fate Associated with DNA Damage

Stochasticity of Intranuclear Biochemical Reaction Processes Controls the Final Decision of Cell Fate Associated with DNA Damage

A massive integrative mathematical model of DNA double-strand break (DSB) generation, DSB repair system, p53 signaling network, and apoptosis induction pathway was constructed to explore the dominant factors of unknown criteria of cell fate decision. In the proposed model, intranuclear reactions wer...

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Main Authors: Iwamoto, Kazunari, Hamada, Hiroyuki, Eguchi, Yukihiro, Okamoto, Masahiro
Format: Online
Language:English
Published: Public Library of Science 2014
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086823/
id pubmed-4086823
recordtype oai_dc
spelling pubmed-40868232014-07-14 Stochasticity of Intranuclear Biochemical Reaction Processes Controls the Final Decision of Cell Fate Associated with DNA Damage Iwamoto, Kazunari Hamada, Hiroyuki Eguchi, Yukihiro Okamoto, Masahiro Research Article A massive integrative mathematical model of DNA double-strand break (DSB) generation, DSB repair system, p53 signaling network, and apoptosis induction pathway was constructed to explore the dominant factors of unknown criteria of cell fate decision. In the proposed model, intranuclear reactions were modeled as stochastic processes and cytoplasmic reactions as deterministic processes, and both reaction sets were simulated simultaneously. The simulated results at the single-cell level showed that the model generated several sustained oscillations (pulses) of p53, Mdm2, ATM, and Wip1, and cell-to-cell variability in the number of p53 pulses depended on IR intensity. In cell populations, the model generated damped p53 oscillations, and IR intensity affected the amplitude of the first p53 oscillation. Cells were then subjected to the same IR dose exhibiting apoptosis induction variability. These simulated results are in quantitative agreement with major biological findings observed in human breast cancer epithelial MCF7, NIH3T3, and fibrosarcoma cells, demonstrating that the proposed model was concededly biologically appropriate. Statistical analysis of the simulated results shows that the generation of multiple p53 pulses is a prerequisite for apoptosis induction. Furthermore, cells exhibited considerable individual variability in p53 dynamics, which correlated with intrinsic apoptosis induction. The simulated results based on the proposed model demonstrated that the stochasticity of intranuclear biochemical reaction processes controls the final decision of cell fate associated with DNA damage. Applying stochastic simulation to an exploration of intranuclear biochemical reaction processes is indispensable in enhancing the understanding of the dynamic characteristics of biological multi-layered systems of higher organisms. Public Library of Science 2014-07-08 /pmc/articles/PMC4086823/ /pubmed/25003668 http://dx.doi.org/10.1371/journal.pone.0101333 Text en © 2014 Iwamoto et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Iwamoto, Kazunari
Hamada, Hiroyuki
Eguchi, Yukihiro
Okamoto, Masahiro
spellingShingle Iwamoto, Kazunari
Hamada, Hiroyuki
Eguchi, Yukihiro
Okamoto, Masahiro
Stochasticity of Intranuclear Biochemical Reaction Processes Controls the Final Decision of Cell Fate Associated with DNA Damage
author_facet Iwamoto, Kazunari
Hamada, Hiroyuki
Eguchi, Yukihiro
Okamoto, Masahiro
author_sort Iwamoto, Kazunari
title Stochasticity of Intranuclear Biochemical Reaction Processes Controls the Final Decision of Cell Fate Associated with DNA Damage
title_short Stochasticity of Intranuclear Biochemical Reaction Processes Controls the Final Decision of Cell Fate Associated with DNA Damage
title_full Stochasticity of Intranuclear Biochemical Reaction Processes Controls the Final Decision of Cell Fate Associated with DNA Damage
title_fullStr Stochasticity of Intranuclear Biochemical Reaction Processes Controls the Final Decision of Cell Fate Associated with DNA Damage
title_full_unstemmed Stochasticity of Intranuclear Biochemical Reaction Processes Controls the Final Decision of Cell Fate Associated with DNA Damage
title_sort stochasticity of intranuclear biochemical reaction processes controls the final decision of cell fate associated with dna damage
description A massive integrative mathematical model of DNA double-strand break (DSB) generation, DSB repair system, p53 signaling network, and apoptosis induction pathway was constructed to explore the dominant factors of unknown criteria of cell fate decision. In the proposed model, intranuclear reactions were modeled as stochastic processes and cytoplasmic reactions as deterministic processes, and both reaction sets were simulated simultaneously. The simulated results at the single-cell level showed that the model generated several sustained oscillations (pulses) of p53, Mdm2, ATM, and Wip1, and cell-to-cell variability in the number of p53 pulses depended on IR intensity. In cell populations, the model generated damped p53 oscillations, and IR intensity affected the amplitude of the first p53 oscillation. Cells were then subjected to the same IR dose exhibiting apoptosis induction variability. These simulated results are in quantitative agreement with major biological findings observed in human breast cancer epithelial MCF7, NIH3T3, and fibrosarcoma cells, demonstrating that the proposed model was concededly biologically appropriate. Statistical analysis of the simulated results shows that the generation of multiple p53 pulses is a prerequisite for apoptosis induction. Furthermore, cells exhibited considerable individual variability in p53 dynamics, which correlated with intrinsic apoptosis induction. The simulated results based on the proposed model demonstrated that the stochasticity of intranuclear biochemical reaction processes controls the final decision of cell fate associated with DNA damage. Applying stochastic simulation to an exploration of intranuclear biochemical reaction processes is indispensable in enhancing the understanding of the dynamic characteristics of biological multi-layered systems of higher organisms.
publisher Public Library of Science
publishDate 2014
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086823/
_version_ 1613109962966302720

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