Bistable biochemical switching and the control of the events of the cell cycle*

Thron, C. D.

doi:10.1038/sj.onc.1201190

Cited by 64 publications

(65 citation statements)

References 36 publications

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“…Bistability has been observed in the budding yeast cell cycle where, under identical culture conditions, a cell may arrest stably in either G 1 phase (low Cdk1 activity) or S͞G 2 ͞M phase (high Cdk1 activity), depending on how the culture is prepared (26). In this study, we demonstrate bistability and hysteresis in frog egg extracts, suggesting that these dynamical properties of the Cdk control system may indeed be common regulatory features of eukaryotic cell cycles, as predicted (17,(20)(21)(22)(23).…”

supporting

confidence: 73%

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Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts

Wang

Moore

Chen

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

462

433

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Cells progressing through the cell cycle must commit irreversibly to mitosis without slipping back to interphase before properly segregating their chromosomes. A mathematical model of cell-cycle progression in cell-free egg extracts from frog predicts that irreversible transitions into and out of mitosis are driven by hysteresis in the molecular control system. Hysteresis refers to toggle-like switching behavior in a dynamical system. In the mathematical model, the toggle switch is created by positive feedback in the phosphorylation reactions controlling the activity of Cdc2, a protein kinase bound to its regulatory subunit, cyclin B. To determine whether hysteresis underlies entry into and exit from mitosis in cell-free egg extracts, we tested three predictions of the NovakTyson model. (i) The minimal concentration of cyclin B necessary to drive an interphase extract into mitosis is distinctly higher than the minimal concentration necessary to hold a mitotic extract in mitosis, evidence for hysteresis. (ii) Unreplicated DNA elevates the cyclin threshold for Cdc2 activation, indication that checkpoints operate by enlarging the hysteresis loop. (iii) A dramatic ''slowing down'' in the rate of Cdc2 activation is detected at concentrations of cyclin B marginally above the activation threshold. All three predictions were validated. These observations confirm hysteresis as the driving force for cell-cycle transitions into and out of mitosis.

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supporting

confidence: 73%

“…1a (17,(20)(21)(22)(23), there is another theoretically plausible explanation for switch-like behavior at mitosis. Periodic cyclin degradation could be driven by a time-delayed negative feedback loop involving Cdc2 activation of Fizzy, without participation from Wee1 and Cdc25.…”

mentioning

confidence: 99%

Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts

Wang

Moore

Chen

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

462

433

View full text Add to dashboard Cite

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“…Lastly, we should mention that other investigators (Tyson et al, 1995;Thron, 1997) have proposed a di erent basis for checkpoint behaviour, namely, bistability which is de®ned as the coexistence of two stable steady states under the same set of parameters; the checkpoint in this case operates by switching the system from one stable steady state to another stable steady state. Note that the coupled PD cycles involving MPF, Cdc25 and Wee1 can be shown to generate bistability when other reactions are included (Novak and Tyson, 1993).…”

Section: Resultsmentioning

confidence: 99%

“…Note that the coupled PD cycles involving MPF, Cdc25 and Wee1 can be shown to generate bistability when other reactions are included (Novak and Tyson, 1993). As de®ned in this paper, a checkpoint mechanism is not necessarily the same as the mechanism intrinsic to the transition from one cell cycle event to the next; bistability, and the associated phenomenon of hysteresis, is an attractive kinetic model for cell cycle transitions because it`ensures that committment to the next phase of the cell cycle is complete and irrevocable' (Thron, 1997). However, we have limited the investigation presented in this paper to points in the cell cycle engine where extrinsic checkpoint pathways could operate.…”

Section: Resultsmentioning

confidence: 99%

Instabilities in phosphorylation-dephosphorylation cascades and cell cycle checkpoints

Aguda

1999

Oncogene

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“…Assuming rapid binding between repressors and activators, the fraction of activators that are not sequestered by the repressors and that are thus transcriptionally active is described by following protein-sequestration function (Fig. 1d) [59,[70][71][72]:…”

Section: Introductionmentioning

confidence: 99%

Protein sequestration versus Hill‐type repression in circadian clock models

Kim¹

2016

IET syst. biol.

107

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Circadian (~24hr) clocks are self-sustained endogenous oscillators with which organisms keep track of daily and seasonal time. Circadian clocks frequently rely on interlocked transcriptionaltranslational feedback loops to generate rhythms that are robust against intrinsic and extrinsic perturbations. To investigate the dynamics and mechanisms of the intracellular feedback loops in circadian clocks, a number of mathematical models have been developed. The majority of the models use Hill functions to describe transcriptional repression in a way that is similar to the Goodwin model. Recently, a new class of models with protein sequestration-based repression has been introduced. Here, we discuss how this new class of models differs dramatically from those based on Hill-type repression in several fundamental aspects: conditions for rhythm generation, robust network designs and the periods of coupled oscillators. Consistently, these fundamental properties of circadian clocks also differ among Neurospora, Drosophila, and mammals depending on their key transcriptional repression mechanisms (Hill-type repression or protein sequestration). Based on both theoretical and experimental studies, this review highlights the importance of careful modeling of transcriptional repression mechanisms in molecular circadian clocks.

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Bistable biochemical switching and the control of the events of the cell cycle*

Cited by 64 publications

References 36 publications

Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts

Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts

Instabilities in phosphorylation-dephosphorylation cascades and cell cycle checkpoints

Protein sequestration versus Hill‐type repression in circadian clock models

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