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Proceedings of the National Academy of Sciences, Vol 88, 9107-9111, Copyright © 1991 by National Academy of Sciences
A Goldbeter
A minimal model for the mitotic oscillator is presented. The model, built
on recent experimental advances, is based on the cascade of
post-translational modification that modulates the activity of cdc2 kinase
during the cell cycle. The model pertains to the situation encountered in
early amphibian embryos, where the accumulation of cyclin suffices to
trigger the onset of mitosis. In the first cycle of the bicyclic cascade
model, cyclin promotes the activation of cdc2 kinase through reversible
dephosphorylation, and in the second cycle, cdc2 kinase activates a cyclin
protease by reversible phosphorylation. That cyclin activates cdc2 kinase
while the kinase triggers the degradation of cyclin has suggested that
oscillations may originate from such a negative feedback loop [Felix, M.
A., Labbe, J. C., Doree, M., Hunt, T. & Karsenti, E. (1990) Nature (London)
346, 379-382]. This conjecture is corroborated by the model, which
indicates that sustained oscillations of the limit cycle type can arise in
the cascade, provided that a threshold exists in the activation of cdc2
kinase by cyclin and in the activation of cyclin proteolysis by cdc2
kinase. The analysis shows how mitotic oscillations may readily arise from
time lags associated with these thresholds and from the delayed negative
feedback provided by cdc2-induced cyclin degradation. A mechanism for the
origin of the thresholds is proposed in terms of the phenomenon of
zero-order ultrasensitivity previously described for biochemical systems
regulated by covalent modification.
ARTICLE
A Minimal Cascade Model for the Mitotic Oscillator Involving Cyclin and cdc2 Kinase
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