Journal
JOURNAL OF THEORETICAL BIOLOGY
Volume 283, Issue 1, Pages 103-112Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jtbi.2011.05.026
Keywords
Liver regeneration; Mitosis; Bandpass filter; G2 delay; Cyclin
Categories
Funding
- German Ministry Federal Ministry of Education and Research (BMBF) [0313078A]
- Deutsche Forschungsgesellschaft (DFG) [SFB 618]
- Project-Team INRIA Dracula (France)
- French National Research Agency [ANR-09-JCJC-0100-01]
- Rhone-Alpes Complex Systems Institute (IXXI, France)
- Agence Nationale de la Recherche (ANR) [ANR-09-JCJC-0100] Funding Source: Agence Nationale de la Recherche (ANR)
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The process of cell division in mammalian cells is orchestrated by cell-cycle-dependent oscillations of cyclin protein levels. Cyclin levels are controlled by redundant transcriptional, post-translational and degradation feedback loops. How each of these separate loops contributes to the regulation of the key cell cycle events and to the connection between the G1-S transition and the subsequent mitotic events is under investigation. Here, we present an integrated computational model of the mammalian cell cycle based on the sequential activation of cyclins. We validate the model against experimental data on liver cells (hepatocytes), which undergo one or two rounds of synchronous circadian-clock gated cell divisions during liver regeneration, after partial hepatectomy (PH). The model exhibits bandpass filter properties that allow the system to ignore strong but transient, or sustained but weak damages after PH. Bifurcation analysis of the model suggests two different threshold mechanisms for the progression of the cell through mitosis. These results are coherent with the notion that the mitotic exit in mammalian cells is bistable, and suggests that Cdc20 homologue 1 (Cdh1) is an important regulator of mitosis. Regulation by Cdh1 also explains the observed G2/M phase prolongation after hepatocyte growth factor (HGF) stimulation during S phase. (C) 2011 Elsevier Ltd. All rights reserved.
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