Model Predicts Cell-Cycle Behavior

Abstract

An intuitive understanding of the control of entry of cells into mitosis has been difficult to achieve, because the signaling networks contain multiple feedback loops. Thus, this well-studied system is an ideal target for a combined approach in which computational modeling and experiment are joined to clarify how such signaling circuitry really works. In Xenopus eggs, the cyclin B-Cdc2 complex drives cells into mitosis. The protein kinase Wee1 inhibits Cdc2 activity, but the active Cdc2 protein kinase phosphorylates Wee1 and thus inhibits its own inhibitor and creates a positive-feedback loop. Active Cdc2 also phosphorylates and activates the phosphatase Cdc25. Because Cdc25 is an activator of Cdc2, this creates another positive-feedback loop. These properties presumably help the cell to move, when appropriate, irreversibly into mitosis. Modeling of these biochemical processes with differential equations by J. J. Tyson and colleagues predicted that one key property of the transition into mitosis is that the amount of activity of Cdc2 required to cause the cell to enter mitosis would be greater that the amount of activity necessary to keep the cell mitosis once the process begins, a phenomenon known as hysteresis. But the true test of the model comes when the prediction is taken back to the laboratory. Sha et al. tested the predicted hysteretic behavior in Xenopus egg extracts and found that this and other characteristics, like an increase in the threshold for entry into mitosis in the presence of unreplicated DNA, were confirmed. As Solomon notes in aa commentary on the paper, such collaboration between computational and experimental approaches is likely to further enhance our understanding of cell-cycle control and of many other signaling processes. W. Sha, J. Moore, K. Chen, A. D. Lassaletta, C.-S. Yi, J. J. Tyson, J. C. Sible, Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts. Proc. Natl. Acad. Sci. U.S.A. 100 , 975-980 (2003) [Abstract] [Full Text] M. J. Solomon, Hysteresis meets the cell cycle. Proc. Natl. Acad. Sci. U.S.A. 100 , 771-772 (2003) [Full Text]