title: Robustness of cell cycle control and flexible orders of signaling events.
abstract: The highly robust control of cell cycles in eukaryotes enables cells to undergo strictly ordered G1/S/G2/M phases and respond adaptively to regulatory signals; however the nature of the robustness remains obscure. Specifically, it is unclear whether events of signaling should be strictly ordered and whether some events are more robust than others. To quantitatively address the two questions, we have developed a novel cell cycle model upon experimental observations. It contains positive and negative E2F proteins and two Cdk inhibitors, and is parameterized, for the first time, to generate not only oscillating protein concentrations but also periodic signaling events. Events and their orders reconstructed under varied conditions indicate that proteolysis of cyclins and Cdk complexes by APC and Skp2 occurs highly robustly in a strict order, but many other events are either dispensable or can occur in flexible orders. These results suggest that strictly ordered proteolytic events are essential for irreversible cell cycle progression and the robustness of cell cycles copes with flexible orders of signaling events, and unveil a new and important dimension to the robustness of cell cycle control in particular and to biological signaling in general.
authors.affiliation: Bioinformatics Section, School of Basic Medical Sciences, Southern Medical University, Shatai Road, Guangzhou, 510515, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.affiliation: MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK.
authors.forename: Yanlan
authors.initials: Y
authors.lastname: Mao
mesh_terms: D000465:Algorithms; D002453:Cell Cycle; D059447:Cell Cycle Checkpoints; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000378:metabolism; D008954:Models, Biological; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D050687:E2F1 Transcription Factor; D018844:Cyclin-Dependent Kinases