title: The Cdk1-APC/C cell cycle oscillator circuit functions as a time-delayed, ultrasensitive switch.
abstract: Despite the complexity and variety of biological oscillators, their core design invariably includes an essential negative feedback loop. In the Xenopus laevis embryonic cell cycle oscillator, this loop consists of the kinase cyclin B-Cdk1 and the ubiquitin ligase APC/C(Cdc20); active Cdk1 activates APC/C(Cdc20), which then brings about cyclin B degradation and inactivates Cdk1. Here we ask how this negative feedback loop functions quantitatively, with the aim of understanding what mechanisms keep the Cdk1-APC/C(Cdc20) system from settling into a stable steady state with intermediate levels of Cdk1 and APC/C(Cdc20) activity. We found that the system operates as a time-delayed, digital switch, with a time lag of ∼ 15 min between Cdk1 and APC/C(Cdc20) activation and a tremendously high degree of ultrasensitivity (n(H)≈17). Computational modelling shows how these attributes contribute to the generation of robust, clock-like oscillations. Principles uncovered here may also apply to other activator-repressor oscillators and help in designing robust synthetic clocks.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, California 94305-5174, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Yang
authors.forename: James E
authors.initials: JE
authors.lastname: Ferrell
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D064199:Cdc20 Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D019295:Computational Biology / Q000379:methods; D003198:Computer Simulation; D019925:Cyclin A / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D004789:Enzyme Activation; D057075:Enzyme Assays; D025461:Feedback, Physiological; D008954:Models, Biological; D010063:Ovum / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D010766:Phosphorylation; D025941:Protein Interaction Mapping / Q000379:methods; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D059748:Proteolysis; D013997:Time Factors; D054875:Ubiquitination; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis / Q000378:metabolism*
chemical_list: C503725:CCNA2 protein, Xenopus; D064199:Cdc20 Proteins; C577501:Cdc20 protein, Xenopus; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056744:Cyclin B1; D029867:Xenopus Proteins; C530005:WEE1 protein, Xenopus; D011505:Protein-Tyrosine Kinases; D016203:CDC2 Protein Kinase