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Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts
Wei Sha*,
Jonathan Moore,
Katherine Chen*,
Antonio D. Lassaletta*,
Chung-Seon Yi*,
John J. Tyson*, and
Jill C. Sible*,
*Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0406; and Cancer Research UK London Research Institute, Clare Hall Labs, South Mimms, Herts, EN6 3LD, United Kingdom
Received for publication September 3, 2002.
Abstract:
Cells progressing through the cell cycle must commit irreversiblyto mitosis without slipping back to interphase before properlysegregating their chromosomes. A mathematical model of cell-cycleprogression in cell-free egg extracts from frog predicts thatirreversible transitions into and out of mitosis are drivenby hysteresis in the molecular control system. Hysteresis refersto toggle-like switching behavior in a dynamical system. Inthe mathematical model, the toggle switch is created by positivefeedback in the phosphorylation reactions controlling the activityof Cdc2, a protein kinase bound to its regulatory subunit, cyclinB. To determine whether hysteresis underlies entry into andexit from mitosis in cell-free egg extracts, we tested threepredictions of the Novak–Tyson model. (i) The minimalconcentration of cyclin B necessary to drive an interphase extractinto mitosis is distinctly higher than the minimal concentrationnecessary to hold a mitotic extract in mitosis, evidence forhysteresis. (ii) Unreplicated DNA elevates the cyclin thresholdfor Cdc2 activation, indication that checkpoints operate byenlarging the hysteresis loop. (iii) A dramatic "slowing down"in the rate of Cdc2 activation is detected at concentrationsof cyclin B marginally above the activation threshold. All threepredictions were validated. These observations confirm hysteresisas the driving force for cell-cycle transitions into and outof mitosis.
To whom correspondence should be addressed. E-mail: siblej{at}vt.edu.
Edited by Thomas D. Pollard, Yale University, New Haven, CT,and approved November 21, 2002
This paper was submitted directly (Track II) to the PNAS office.
Control of Cell Proliferation, Organ Growth, and DNA Damage Response Operate Independently of Dephosphorylation of the Arabidopsis Cdk1 Homolog CDKA;1.
N. Dissmeyer, A. K. Weimer, S. Pusch, K. De Schutter, C. L. A. Kamei, M. K. Nowack, B. Novak, G.-L. Duan, Y.-G. Zhu, L. De Veylder, et al. (2009)
PLANT CELL
21, 3641-3654
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To whom correspondence should be addressed. E-mail: siblej{at}vt.edu. 
,
Katherine Chen*,
Antonio D. Lassaletta*,
Chung-Seon Yi*,
John J. Tyson*, and
Jill C. Sible*
