Mathematical modeling of G2/M phase in the cell cycle with involving the p53/Mdm2 oscillation system

Yoshihiko Tashima, Yu Kisaka, Taizo Hanai, Hiroyuki Hamada, Yukihiro Eguchi, Masahiro Okamoto

Research output: Chapter in Book/Report/Conference proceedingConference contribution

4 Citations (Scopus)

Abstract

In the cell cycle, the disruption of a checkpoint control mechanism for G2/M phase which monitors DNA damages is one of the triggers for oncogenic transformation. The major event of this mechanism is the p53/Mdm2 signaling pathway-mediated repression of M-phase Promoting Factor (MPF) activation. With the occurring some DNA damages, the protein levels of the p53/Mdm2 shows the oscillation, and the temporal response of the MPF activation delays. However, the detailed interactions between the p53/Mdm2 oscillation and the MPF activation are still unclear biologically. In this study, we designed a mathematical model which can realize the qualitative temporal dynamics of G2/M phase involving the p53/Mdm2 signaling pathway. Moreover we performed some simulations and comprehensive system analysis in order to evaluate the robustness and to explore the dominant control factors of the model. A novel mathematical model (proposed model) was designed by integrating a model for the MPF activation with the p53/Mdm2 signaling pathway. The numerical solutions of the dynamics with employing the proposed model showed the qualitative correspondence with the p53/Mdm2 oscillation and the temporal delay of the MPF activation, which were observed experimentally. Without the assumption of DNA damage, the sensitivity of kinetic parameters of this model was low, and the model system showed high stability. In the case of some DNA damages, however, the sensitivity became to be higher, and the model system showed instability. Thus, we can evaluate that some DNA damages can easily affect the stability of the checkpoint control mechanism. A defective function of Wee1 phosphorylation which affects the dynamics of MPF inhibited the DNA damagemediated temporal delay of the MPF activation. Since a chronic decline of protein level for Wee1 was observed in tumor cells, we proposed that the phosphorylation is one of the dominant factors for the checkpoint control mechanism in G2/M phase.

Original languageEnglish
Title of host publicationIFMBE Proceedings
EditorsSun I. Kim, Tae Suk Suh
PublisherSpringer Verlag
Pages197-200
Number of pages4
Edition1
ISBN (Print)9783540368397
DOIs
Publication statusPublished - 2007
Event10th World Congress on Medical Physics and Biomedical Engineering, WC 2006 - Seoul, Korea, Republic of
Duration: Aug 27 2006Sep 1 2006

Publication series

NameIFMBE Proceedings
Number1
Volume14
ISSN (Print)1680-0737
ISSN (Electronic)1433-9277

Other

Other10th World Congress on Medical Physics and Biomedical Engineering, WC 2006
CountryKorea, Republic of
CitySeoul
Period8/27/069/1/06

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Biomedical Engineering

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