Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Algorithms
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Amanitins / pharmacology
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Animals
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Biological Clocks / physiology
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Blastula / physiology
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Blotting, Western
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CDC2-CDC28 Kinases / genetics
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CDC2-CDC28 Kinases / metabolism*
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Cell Cycle / physiology
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Cell Cycle Proteins / metabolism
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Cell Cycle Proteins / pharmacology
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Cell Cycle Proteins / physiology
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Checkpoint Kinase 1
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Computational Biology
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Cyclin E / genetics
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Cyclin E / metabolism*
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p27
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Embryo, Nonmammalian / metabolism
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Embryonic Development
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Feedback, Physiological / physiology
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Kinetics
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Models, Biological*
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Models, Theoretical
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Nuclear Proteins*
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Phosphorylation
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Protein Kinases / genetics
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Protein Kinases / metabolism
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Protein-Tyrosine Kinases / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Transcription, Genetic / drug effects
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Tumor Suppressor Proteins / pharmacology
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Tumor Suppressor Proteins / physiology
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Xenopus Proteins
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Xenopus laevis / embryology*
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Xenopus laevis / genetics
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cdc25 Phosphatases / metabolism
Substances
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Amanitins
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Cell Cycle Proteins
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Cyclin E
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Nuclear Proteins
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RNA, Messenger
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Tumor Suppressor Proteins
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Xenopus Proteins
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Xicl protein, Xenopus
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Cyclin-Dependent Kinase Inhibitor p27
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Protein Kinases
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WEE1 protein, Xenopus
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Protein-Tyrosine Kinases
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Checkpoint Kinase 1
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CDC2-CDC28 Kinases
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Cdk2 protein, Xenopus
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Cyclin-Dependent Kinase 2
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cdc25 Phosphatases