The CDK1–cyclin regulatory network. (A) The network includes a negative feedback loop involving the anaphase-promoting complex (APC) and two positive feedback loops. The WEE1 loop inhibits CDK1 and the CDC25 loop promotes activation of CDK1. (B) The two positive feedback loops can be studied in isolation by adding a form of cyclin that cannot be degraded by the APC. In this situation, CDK1 displays either bistable (light blue) or monostable (dark blue) activity states. Solid and dotted lines represent stable and unstable equilibria, respectively. At low cyclin concentrations (1), WEE1 inhibits CDK1, CDC25 is inactive and CDK1 activity is low. At higher cyclin concentrations, two stable levels of CDK1 activity exist, a property known as bistability. However, the presence of the system in either of these stable states is dependent on the previous state of the system (hysteresis). Consequently CDK1 remains inactive. At a threshold cyclin concentration (2), the system becomes monostable as WEE1 inhibition is removed and CDC25 is activated. The system then changes rapidly to a stable equilibrium with high CDK1 activity (3). CDK1 activity will remain high until cyclin levels are reduced sufficiently for the left-hand monostable solution (4) to be reached.