Instabilities in phosphorylation-dephosphorylation cascades and cell cycle checkpoints

Aguda, BD

doi:10.1038/sj.onc.1202462

Cited by 26 publications

(22 citation statements)

References 19 publications

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“…Fig. 1 bears superficial similarity to other published models of mammalian cell-cycle controls (Hatzimanikatis et al, 1995;Obeyesekere et al, 1997;Kohn, 1998;Aguda, 1999;Qu et al, 2003b), because everyone agrees on the principal molecular components and their interactions in G1 phase. Nonetheless, several features set our model apart.…”

Section: Article In Presssupporting

confidence: 75%

“…The model is based on the idea that G1 events are driven by the ''switching'' properties of positive-feedback loops and antagonistic interactions (Tyson et al, 1995;Kohn, 1998;Novak et al, 1998b;Aguda, 1999;Thron, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…Many people have recognized this need and called for new theoretical approaches to molecular biology (Maddox, 1994;Hartwell et al, 1999;Lander and Weinberg, 2000;Nurse, 2000;Gilman and Arkin, 2002;Kumar and Feidler, 2003). Although everyone seems to agree that present theoretical techniques are not ready for a ''frontal assault'' on Kohn's (1999) circuit diagram or a comprehensive explanation of the physiology of mammalian cell division, several groups of theoretical biologists have risen to the challenge of modeling parts of the mammalian cell cycle (Hatzimanikatis et al, 1995;Obeyesekere et al, 1997;Kohn, 1998;Aguda, 1999;Thron, 1999;Qu et al, 2003b). A recent model Table 1 Glossary Cyclin-dependent kinase (Cdk1, Cdk2, etc.…”

Section: Biochemical Circuit Theorymentioning

confidence: 99%

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A model for restriction point control of the mammalian cell cycle

Novák

Tyson

2004

Journal of Theoretical Biology

268

279

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Section: Article In Presssupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Section: Biochemical Circuit Theorymentioning

confidence: 99%

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A model for restriction point control of the mammalian cell cycle

Novák

Tyson

2004

Journal of Theoretical Biology

268

279

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“…Even though the present model does not apply directly to the cell cycle, it suggests that the stepwise progression along the di!erent phases of the cycle, temporarily halted by the transient action of inhibitors, corresponds to the dynamics of an impeded limit-cycle oscillator which is transiently moved into a stable steady state in the presence of such inhibitors and resumes its periodic operation as soon as they are removed. This view can be related to conclusions drawn by Aguda (1999a, b) from theoretical studies on the nature of checkpoints in the cell cycle. By analysing models involving phosphorylation}dephospho-rylation cycles centered around the kinase cdc2, the phosphatase cdc25 and the kinase wee1, this author showed that the G2-M checkpoint may be associated with control of the passage through a critical parameter value corresponding to a transcritical bifurcation point beyond which a new steady state is established.…”

Section: Discussionmentioning

confidence: 99%

“…11, left panel) resembles an abstract extension of simpler models to a ring of phosphorylation} dephosphorylation cycles, suggested by Aguda 184 D. GONZE AND A. GOLDBETER (see Fig. 6 in Aguda, 1999a). The present analysis focused explicitly on the oscillatory dynamics and the multistability properties of such networks subjected to a variety of forward or/and backward regulatory interactions.…”

Section: Discussionmentioning

confidence: 99%

A Model for a Network of Phosphorylation–dephosphorylation Cycles Displaying the Dynamics of Dominoes and Clocks

Gonze¹,

Goldbeter²

2001

Journal of Theoretical Biology

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We consider a model for a network of phosphorylation}dephosphorylation cycles coupled through forward and backward regulatory interactions, such that a protein phosphorylated in a given cycle activates the phosphorylation of a protein by a kinase in the next cycle as well as the dephosphorylation of a protein by a phosphatase in a preceding cycle. The network is cyclically organized in such a way that the protein phosphorylated in the last cycle activates the kinase in the "rst cycle. We study the dynamics of the network in the presence of both forward and backward coupling, in conditions where a threshold exists in each cycle in the amount of protein phosphorylated as a function of the ratio of kinase to phosphatase maximum rates. We show that this system can display sustained (limit-cycle) oscillations in which each cycle in the pathway is successively turned on and o!, in a sequence resembling the fall of a series of dominoes. The model thus provides an example of a biochemical system displaying the dynamics of dominoes and clocks (Murray & Kirschner, 1989). It also shows that a continuum of clock waveforms exists of which the fall of dominoes represents a limit. When the cycles in the network are linked through only forward (positive) coupling, bistability is observed, while in the presence of only backward (negative) coupling, the system can display multistability or oscillations, depending on the number of cycles in the network. Inhibition or activation of any kinase or phosphatase in the network immediately stops the oscillations by bringing the system into a stable steady state; oscillations resume when the initial value of the kinase or phosphatase rate is restored. The progression of the system on the limit cycle can thus be temporarily halted as long as an inhibitor is present, much as when a domino is held in place. These results suggest that the eukaryotic cell cycle, governed by a network of phosphorylation}dephosphorylation reactions in which the negative control of cyclin-dependent kinases plays a prominent role, behaves as a limit-cycle oscillator impeded in the presence of inhibitors. We contrast the case where the sequence of domino-like transitions constitutes the clock with the case where the sequence of transitions is passively coupled to a biochemical oscillator operating as an independent clock. Academic Press

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Data Sources and Computational Approaches for Generating Models of Gene Regulatory Networks

Aguda

Crăciun

Çetin-Atalay

2005

Reviews in Computational Chemistry

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Whole-cell modeling platforms Ontology for modeling multi-scale and incomplete networks An ontology for cellular processes The PATIKA pathway ontology Extracting Models from Pathways Databases Pathway and Dynamic Analysis Tools for GRNs Global network properties Recurring network motifs Identifying pathway channels in networks: extreme pathway analysis Network stability analysis Predicting dynamics & bistability from network structure alone Concluding Remarks 3

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Instabilities in phosphorylation-dephosphorylation cascades and cell cycle checkpoints

Cited by 26 publications

References 19 publications

A model for restriction point control of the mammalian cell cycle

A model for restriction point control of the mammalian cell cycle

A Model for a Network of Phosphorylation–dephosphorylation Cycles Displaying the Dynamics of Dominoes and Clocks

Data Sources and Computational Approaches for Generating Models of Gene Regulatory Networks

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