Reaction scheme for the minimal Cdk network driving the cell cycle in fission yeast.

Abstract

<p>Solid lines represent biochemical reactions, while dashed lines define catalytic effects. Only one Cdk:cyclin complex (the fusion protein Cdc13-L-Cdc2, referred to as MPF) controls the successive progression through DNA replication and mitosis. MPF activity can be regulated by reversible association with the Cdk inhibitor Rum1, as well as by phosphorylation and dephosphorylation by the inhibitory kinase Wee1 and the activating phosphatase Cdc25, respectively. MPF inhibits Rum1 and Wee1, while it activates Cdc25. These regulatory interactions create mutual inhibitions between MPF and Rum1 and between MPF and Wee1, and a mutual activation loop between MPF and Cdc25. In the model, we consider that the phosphorylated form of MPF, MPF_P, is still partially active (5% of the activity of MPF). Thus, MPF_P can inhibit Rum1 and regulate Wee1 and Cdc25. We assume that MPF and Rum1 form a stable complex, but the binding of Rum1 to MPF_P is much less strong. Active MPF promotes its own degradation through a delayed negative feedback loop involving Slp1 and the APC (Anaphase Promoting Complex). This negative feedback loop, which causes the destruction of MPF at the end of mitosis, is critical to generating sustained oscillations in MPF activity that drive repetitive cycles of DNA replication followed by mitosis. <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004056#pcbi.1004056.s001" target="_blank">S1 Table</a> defines the different proteins involved in the model. The “time delay” in the figure is implemented in the differential equations by an Intermediary Enzyme (IE) between MPF and Slp1.</p