Hysteresis meets the cell cycle.

W hat, you may well ask, does hysteresis have to do with cell cycle progression? The last time most of us heard about hysteresis was in the context of the ferromagnetism that underlies tape players and floppy drives. In general, hysteresis means that it takes more of something to push a system from state A to state B than it does to keep the system in state B. Sha et al. (1) report in this issue of PNAS that the cell cycle of Xenopus egg extracts exhibits hysteresis in that the amount of cyclin needed to induce entry into mitosis is larger than the amount of cyclin needed to hold the extract in mitosis. This effect creates a nice bistable system with a ratchet to prevent slipping back from mitosis to interphase. This work also represents an excellent marriage of theory and experiment from the labs of John Tyson and Jill Sible, respectively, at Virginia Polytechnic Institute in Blacksburg. Some background, both experimental and theoretical, is necessary before discussing the importance of the current findings. The eukaryotic cell cycle is driven by sequential activation and inactivation of cyclin-dependent protein kinases (CDKs) (2, 3). The CDK for entry into mitosis is Cdc2. Cdc2 activation requires binding to a regulatory protein (cyclin B) and activating phosphorylation (carried out by CDK-activating kinases, or CAKs). Even in the presence of cyclin and activating phosphorylation, Cdc2 can be inactivated by inhibitory phosphorylations (carried out by the Wee1 and Myt1 protein kinases). Inhibitory phosphorylations are removed by the Cdc25 protein phosphatases, which are the immediate triggers for entry into mitosis. CDKs regulating other cell cycle transitions can in addition be inhibited by direct binding of inhibitory proteins. Mitotic cyclins are subject to ubiquitinmediated degradation at the end of mitosis by the action of the anaphasepromoting complex (APC; an E3, or ubiquitin ligase, of the ubiquitin system). Extremely important to the proper functioning of the cell cycle are checkpoints that ensure that key cell cycle events are not initiated until prior steps are completed. For example, a DNA replication checkpoint prevents Cdc2 activation until DNA replication is complete and the spindle assembly checkpoint prevents cyclin degradation via the APC until all chromosomes are properly aligned on the metaphase plate. Many important advances in understanding entry into and exit from mitosis have come from biochemical studies of Xenopus egg extracts (2). This ‘‘simple’’ system is obtained by crushing frog eggs in the presence of minimal amounts of buffer. These extracts can undergo multiple rapid cell cycles, monitored either by the morphology of added nuclei or by assays of Cdc2 activity. These cell cycles can be driven by