A kinetic model of the cyclin E/Cdk2 developmental timer in Xenopus laevis embryos.
Early cell cycles of Xenopus laevis embryos are characterized by rapid oscillations in the activity of two cyclin-dependent kinases. Cdk1 activity peaks at mitosis, driven by periodic degradation of cyclins A and B. In contrast, Cdk2 activity oscillates twice per cell cycle, despite a constant level of its partner, cyclin E. Cyclin E degrades at a fixed time after fertilization, normally corresponding to the midblastula transition. Based on published data and new experiments, we constructed a mathematical model in which: (1) oscillations in Cdk2 activity depend upon changes in phosphorylation, (2) Cdk2 participates in a negative feedback loop with the inhibitory kinase Wee1; (3) cyclin E is cooperatively removed from the oscillatory system; and (4) removed cyclin E is degraded by a pathway activated by cyclin E/Cdk2 itself. The model's predictions about embryos injected with Xic1, a stoichiometric inhibitor of cyclin E/Cdk2, were experimentally validated.
Ciliberto
Andrea
A
Biology Department, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061-0406, USA. ancilibe@vt.edu
Petrus
Matthew J
MJ
Tyson
John J
JJ
Sible
Jill C
JC
D000465:Algorithms; D000546:Amanitins / Q000494:pharmacology; D000818:Animals; D001683:Biological Clocks / Q000502:physiology; D036703:Blastula / Q000502:physiology; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology; D000071877:Checkpoint Kinase 1; D019295:Computational Biology; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004625:Embryo, Nonmammalian / Q000378:metabolism; D047108:Embryonic Development; D025461:Feedback, Physiological / Q000502:physiology; D007700:Kinetics; D008954:Models, Biological; D008962:Models, Theoretical; D009687:Nuclear Proteins; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000494:pharmacology / Q000502:physiology; D029867:Xenopus Proteins; D014982:Xenopus laevis / Q000196:embryology* / Q000235:genetics; D020687:cdc25 Phosphatases / Q000378:metabolism
D000546:Amanitins; D018797:Cell Cycle Proteins; D019927:Cyclin E; D009687:Nuclear Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D029867:Xenopus Proteins; C493963:Xicl protein, Xenopus; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011494:Protein Kinases; C530005:WEE1 protein, Xenopus; D011505:Protein-Tyrosine Kinases; D000071877:Checkpoint Kinase 1; D042846:CDC2-CDC28 Kinases; C495891:Cdk2 protein, Xenopus; D051357:Cyclin-Dependent Kinase 2; D020687:cdc25 Phosphatases