Mitotic exit in two dimensions.
Metaphase of mitosis is brought about in all eukaryotes by activation of cylin-dependent kinase (Cdk1), whereas exit from mitosis requires down-regulation of Cdk1 activity and dephosphorylation of its target proteins. In budding yeast, the completion of mitotic exit requires the release and activation of the Cdc14 protein-phosphatase, which is kept inactive in the nucleolus during most of the cell cycle. Activation of Cdc14 is controlled by two regulatory networks called FEAR (Cdc fourteen early anaphase release) and MEN (mitotic exit network). We have shown recently that the anaphase promoting protease (separase) is essential for Cdc14 activation, thereby it makes mitotic exit dependent on execution of anaphase. Based on this finding, we have proposed a new model for mitotic exit in budding yeast. Here we explain the essence of the model by phaseplane analysis, which reveals two underlying bistable switches in the regulatory network. One bistable switch is caused by mutual activation (positive feedback) between Cdc14 activating MEN and Cdc14 itself. The mitosis-inducing Cdk1 activity inhibits the activation of this positive feedback loop and thereby controlling this switch. The other irreversible switch is generated by a double-negative feedback (mutual antagonism) between mitosis inducing Cdk1 activity and its degradation machinery (APC(Cdh1)). The Cdc14 phosphatase helps turning this switch in favor of APC(Cdh1) side. Both of these bistable switches have characteristic thresholds, the first one for Cdk1 activity, while the second for Cdc14 activity. We show that the physiological behaviors of certain cell cycle mutants are suggestive for those Cdk1 and Cdc14 thresholds. The two bistable switches turn on in a well-defined order. In this paper, we explain how the activation of Cdc20 (which causes the activation of separase and a decrease of Cdk1 kinase activity) provides an initial trigger for the activation of the MEN-Cdc14 positive feedback loops, which in turn, flips the second irreversible Cdk-APC(Cdh1) switch on the APC(Cdh1) side).
Molecular Network Dynamics Group of Hungarian Academy of Sciences and Budapest University of Technology and Economics, 1111 Budapest Gellert ter 4, Hungary.
Attila
A
Tóth
Ethel
E
Queralt
Frank
F
Uhlmann
Béla
B
Novák
D000705:Anaphase / Q000502:physiology; D064173:Anaphase-Promoting Complex-Cyclosome; D016203:CDC2 Protein Kinase / Q000378:metabolism; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000378:metabolism; D008433:Mathematics; D008938:Mitosis / Q000502:physiology*; D008954:Models, Biological; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D004718:Saccharomycetales / Q000378:metabolism / Q000502:physiology*; D064247:Separase; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism
C074860:CDC14 protein, S cerevisiae; C577495:CDC20 protein, S cerevisiae; C093749:CLB2 protein, S cerevisiae; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D019926:Cyclin B; D005656:Fungal Proteins; D029701:Saccharomyces cerevisiae Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D016203:CDC2 Protein Kinase; D018844:Cyclin-Dependent Kinases; D017027:Protein Tyrosine Phosphatases; D010450:Endopeptidases; C577986:ESP1 protein, S cerevisiae; D064247:Separase