Hysteresis drives cell-cycle transitions in <i>Xenopus laevis</i> egg extracts

TLDR

Cell‑cycle progression requires irreversible commitment to mitosis, and hysteresis—toggle‑like switching in dynamical systems—provides this irreversibility. The study tests whether hysteresis drives entry into and exit from mitosis in cell‑free egg extracts by evaluating predictions of the Novak–Tyson model. A mathematical model of frog egg extracts uses positive feedback in Cdc2–cyclin B phosphorylation to generate a hysteretic toggle switch that predicts irreversible mitotic transitions. Experimental validation showed that cyclin B thresholds for entry and exit differ, unreplicated DNA raises the entry threshold, and activation slows near the threshold, confirming that hysteresis drives mitotic transitions.

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.