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

研究成果: Chapter in Book/Report/Conference proceedingConference contribution

4 被引用数 (Scopus)

抄録

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.

本文言語英語
ホスト出版物のタイトルIFMBE Proceedings
編集者Sun I. Kim, Tae Suk Suh
出版社Springer Verlag
ページ197-200
ページ数4
1
ISBN(印刷版)9783540368397
DOI
出版ステータス出版済み - 2007
イベント10th World Congress on Medical Physics and Biomedical Engineering, WC 2006 - Seoul, 大韓民国
継続期間: 8 27 20069 1 2006

出版物シリーズ

名前IFMBE Proceedings
番号1
14
ISSN(印刷版)1680-0737
ISSN(電子版)1433-9277

その他

その他10th World Congress on Medical Physics and Biomedical Engineering, WC 2006
Country大韓民国
CitySeoul
Period8/27/069/1/06

All Science Journal Classification (ASJC) codes

  • Bioengineering
  • Biomedical Engineering

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