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PNAS 100 (3): 975-980

Copyright © 2003 by the National Academy of Sciences.

From the Cover


Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts

Wei Sha*, Jonathan Moore{dagger}, Katherine Chen*, Antonio D. Lassaletta*, Chung-Seon Yi*, John J. Tyson*, and Jill C. Sible*,{ddagger}

*Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0406; and {dagger}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 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.

{ddagger} To whom correspondence should be addressed. E-mail: siblej{at}

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.

See commentary on page 771.

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