Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts.
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.
Sha
Wei
W
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0406, USA.
Moore
Jonathan
J
Chen
Katherine
K
Lassaletta
Antonio D
AD
Yi
Chung-Seon
CS
Tyson
John J
JJ
Sible
Jill C
JC
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002453:Cell Cycle; D002474:Cell-Free System; D019926:Cyclin B / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015151:Immunoblotting; D008540:Meiosis; D008938:Mitosis; D008962:Models, Theoretical; D009865:Oocytes / Q000378:metabolism*; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D013997:Time Factors; D014982:Xenopus laevis / Q000196:embryology*
D019926:Cyclin B; D004247:DNA; D011494:Protein Kinases; C102333:histone H1 kinase; D016203:CDC2 Protein Kinase