Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts.

TitleHysteresis drives cell-cycle transitions in Xenopus laevis egg extracts.
Publication TypeJournal Article
Year of Publication2003
AuthorsSha W, Moore J, Chen K, Lassaletta AD, Yi C-S, Tyson JJ, Sible JC
JournalProc Natl Acad Sci U S A
Volume100
Issue3
Pagination975-80
Date Published2003 Feb 04
ISSN0027-8424
KeywordsAnimals, CDC2 Protein Kinase, Cell Cycle, Cell-Free System, Cyclin B, DNA, Dose-Response Relationship, Drug, Immunoblotting, Meiosis, Mitosis, Models, Theoretical, Oocytes, Protein Binding, Protein Kinases, Time Factors, Xenopus laevis
Abstract

<p>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.</p>

DOI10.1073/pnas.0235349100
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID12509509
PubMed Central IDPMC298711