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XB-ART-5952
Proc Natl Acad Sci U S A 2003 Feb 04;1003:975-80. doi: 10.1073/pnas.0235349100.
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Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts.

Sha W , Moore J , Chen K , Lassaletta AD , Yi CS , Tyson JJ , Sible JC .


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Cells progressing through the cell cycle must commit irreversibly to mitosis without slipping back to interphase before properly segregating their chromosomes. A mathematical model of cell-cycle progression in cell-free egg extracts from frog predicts that irreversible transitions into and out of mitosis are driven by hysteresis in the molecular control system. Hysteresis refers to toggle-like switching behavior in a dynamical system. In the mathematical model, the toggle switch is created by positive feedback in the phosphorylation reactions controlling the activity of Cdc2, a protein kinase bound to its regulatory subunit, cyclin B. To determine whether hysteresis underlies entry into and exit from mitosis in cell-free egg extracts, we tested three predictions of the Novak-Tyson model. (i) The minimal concentration of cyclin B necessary to drive an interphase extract into mitosis is distinctly higher than the minimal concentration necessary to hold a mitotic extract in mitosis, evidence for hysteresis. (ii) Unreplicated DNA elevates the cyclin threshold for Cdc2 activation, indication that checkpoints operate by enlarging the hysteresis loop. (iii) A dramatic "slowing down" in the rate of Cdc2 activation is detected at concentrations of cyclin B marginally above the activation threshold. All three predictions were validated. These observations confirm hysteresis as the driving force for cell-cycle transitions into and out of mitosis.

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Species referenced: Xenopus laevis
Genes referenced: cdk1

References [+] :
Aguda, A quantitative analysis of the kinetics of the G(2) DNA damage checkpoint system. 1999, Pubmed