Dynamics of mitotic exit
Section snippets
Objectives
Cell cycle events in eukaryotes are regulated by periodic activation and inactivation of a family of cyclin-dependent kinases (Cdk's). Entry into mitosis is initiated by accumulation of Cdk in complexes with B-type cyclins, and exit from mitosis requires inactivation of these Cdk-cyclin complexes and dephosphorylation of Cdk targets. The Cdks are inactivated by Cdc20- and Cdh1-dependent proteolysis, and dephosphorylation is carried out by Cdc14, an essential phosphatase promoting mitotic exit.
Methods
In Fig. 1, we propose a general protein interaction network for regulating mitotic exit pathways in budding yeast. Using basic principles of biochemical kinetics, we transform the wiring diagram into a set of ordinary differential equations. Rate constants are estimated so as to explain right characteristics of all mitotic exit mutants.
Results
Our model provides a rigorous account of the factors affecting the dual exit pathways, called FEAR (Cdc14 early anaphase release) and MEN (mitotic exit network). The model captures the dynamics of mitotic exit in wild-type and mutant yeast cells, including many details of the physiology, biochemistry, and genetics of the process. Although the model is similar to the recent model of Queralt et al (Cell, 2006), we have added new components to account for all observations on FEAR and MEN networks
Conclusion
We propose a novel mechanism for multiphosphorylation of Net1 (an inhibitor of Cdc14) by several kinases: Cdk, Cdc5 (Polo), and Dbf2/Mob1 (through activation of Cdc15). The model explains factors affecting the activation and inactivation of FEAR pathway and MEN pathway in a rigorous way. Understanding how Polo-like kinases fit into the exit pathways is important because Polo-like kinases are being actively pursued as therapeutic targets in the treatment of human cancer.