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A mathematical model of mitotic exit in budding yeast: the role of Polo kinase.

Hancioglu B, Tyson JJ - PLoS ONE (2012)

Bottom Line: Entry into mitosis requires phosphorylation of many proteins targeted by mitotic Cdk, and exit from mitosis requires proteolysis of mitotic cyclins and dephosphorylation of their targeted proteins.The model captures the dynamics of this network in wild-type yeast cells and 110 mutant strains.The model clarifies the roles of Polo-like kinase (Cdc5) in the Cdc14 early anaphase release pathway and in the G-protein regulated mitotic exit network.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America. barish@rice.edu

ABSTRACT
Cell cycle progression in eukaryotes is regulated by periodic activation and inactivation of a family of cyclin-dependent kinases (Cdk's). Entry into mitosis requires phosphorylation of many proteins targeted by mitotic Cdk, and exit from mitosis requires proteolysis of mitotic cyclins and dephosphorylation of their targeted proteins. Mitotic exit in budding yeast is known to involve the interplay of mitotic kinases (Cdk and Polo kinases) and phosphatases (Cdc55/PP2A and Cdc14), as well as the action of the anaphase promoting complex (APC) in degrading specific proteins in anaphase and telophase. To understand the intricacies of this mechanism, we propose a mathematical model for the molecular events during mitotic exit in budding yeast. The model captures the dynamics of this network in wild-type yeast cells and 110 mutant strains. The model clarifies the roles of Polo-like kinase (Cdc5) in the Cdc14 early anaphase release pathway and in the G-protein regulated mitotic exit network.

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Numerical simulation of exit from mitosis in wild-type cells.The four panels show the time courses of ME regulators during a typical Cdc20 ‘block and release’ experiment, which is simulated as follows: the simulation starts at t = −15 min under metaphase-block conditions (cdc20Δ GAL-CDC20 in glucose; ks,20 = 0), and then Cdc20 synthesis is induced (transfer to galactose; ks,20 = 0.015) at t = 0. During the Cdc20-block phase (t<0), free Cdc14 is low due to sequestration by Net1 in RENT, MEN is inactive, and Net1 and RENT are predominantly dephosphorylated because of high activity of PP2A. The steady state levels of Clb2, Cdc5, Net1, RENT and PP2A are close to 1 (arbitrary unit).
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pone-0030810-g002: Numerical simulation of exit from mitosis in wild-type cells.The four panels show the time courses of ME regulators during a typical Cdc20 ‘block and release’ experiment, which is simulated as follows: the simulation starts at t = −15 min under metaphase-block conditions (cdc20Δ GAL-CDC20 in glucose; ks,20 = 0), and then Cdc20 synthesis is induced (transfer to galactose; ks,20 = 0.015) at t = 0. During the Cdc20-block phase (t<0), free Cdc14 is low due to sequestration by Net1 in RENT, MEN is inactive, and Net1 and RENT are predominantly dephosphorylated because of high activity of PP2A. The steady state levels of Clb2, Cdc5, Net1, RENT and PP2A are close to 1 (arbitrary unit).

Mentions: In Figure 2 we simulate ME events based on the differential equations in Table S1, the ‘basal’ set of rate constants for wild-type cells (Table S2), and the initial conditions (Table S3) that represent a cell arrested in metaphase. In this paper, ‘wild type’ refers to cells of the mutant strain cdc20ΔGAL-CDC20, which can be arrested in metaphase by Cdc20-depletion (growth on glucose) and then induced to exit mitosis by adding back Cdc20 (transferring cells from glucose to galactose medium) at t = 0. In Figure 2, as in all simulations, we plot the (scaled) concentrations of representative proteins: Clb2, Cdc5, Cdc14 (released), Cdh1 (active), etc. The simulation is in good agreement with experimental observations of ME in wild-type cells [17]. During metaphase arrest by Cdc20-depletion, Cdc14 is sequestered in RENT, MEN activity is negligible, and all phosphorylated forms of Net1 and RENT are small. The steady state levels of Clb2, Cdc5, Net1, RENT and PP2A are at their peak values, close to 1 (arbitrary unit).


A mathematical model of mitotic exit in budding yeast: the role of Polo kinase.

Hancioglu B, Tyson JJ - PLoS ONE (2012)

Numerical simulation of exit from mitosis in wild-type cells.The four panels show the time courses of ME regulators during a typical Cdc20 ‘block and release’ experiment, which is simulated as follows: the simulation starts at t = −15 min under metaphase-block conditions (cdc20Δ GAL-CDC20 in glucose; ks,20 = 0), and then Cdc20 synthesis is induced (transfer to galactose; ks,20 = 0.015) at t = 0. During the Cdc20-block phase (t<0), free Cdc14 is low due to sequestration by Net1 in RENT, MEN is inactive, and Net1 and RENT are predominantly dephosphorylated because of high activity of PP2A. The steady state levels of Clb2, Cdc5, Net1, RENT and PP2A are close to 1 (arbitrary unit).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3285609&req=5

pone-0030810-g002: Numerical simulation of exit from mitosis in wild-type cells.The four panels show the time courses of ME regulators during a typical Cdc20 ‘block and release’ experiment, which is simulated as follows: the simulation starts at t = −15 min under metaphase-block conditions (cdc20Δ GAL-CDC20 in glucose; ks,20 = 0), and then Cdc20 synthesis is induced (transfer to galactose; ks,20 = 0.015) at t = 0. During the Cdc20-block phase (t<0), free Cdc14 is low due to sequestration by Net1 in RENT, MEN is inactive, and Net1 and RENT are predominantly dephosphorylated because of high activity of PP2A. The steady state levels of Clb2, Cdc5, Net1, RENT and PP2A are close to 1 (arbitrary unit).
Mentions: In Figure 2 we simulate ME events based on the differential equations in Table S1, the ‘basal’ set of rate constants for wild-type cells (Table S2), and the initial conditions (Table S3) that represent a cell arrested in metaphase. In this paper, ‘wild type’ refers to cells of the mutant strain cdc20ΔGAL-CDC20, which can be arrested in metaphase by Cdc20-depletion (growth on glucose) and then induced to exit mitosis by adding back Cdc20 (transferring cells from glucose to galactose medium) at t = 0. In Figure 2, as in all simulations, we plot the (scaled) concentrations of representative proteins: Clb2, Cdc5, Cdc14 (released), Cdh1 (active), etc. The simulation is in good agreement with experimental observations of ME in wild-type cells [17]. During metaphase arrest by Cdc20-depletion, Cdc14 is sequestered in RENT, MEN activity is negligible, and all phosphorylated forms of Net1 and RENT are small. The steady state levels of Clb2, Cdc5, Net1, RENT and PP2A are at their peak values, close to 1 (arbitrary unit).

Bottom Line: Entry into mitosis requires phosphorylation of many proteins targeted by mitotic Cdk, and exit from mitosis requires proteolysis of mitotic cyclins and dephosphorylation of their targeted proteins.The model captures the dynamics of this network in wild-type yeast cells and 110 mutant strains.The model clarifies the roles of Polo-like kinase (Cdc5) in the Cdc14 early anaphase release pathway and in the G-protein regulated mitotic exit network.

View Article: PubMed Central - PubMed

Affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America. barish@rice.edu

ABSTRACT
Cell cycle progression in eukaryotes is regulated by periodic activation and inactivation of a family of cyclin-dependent kinases (Cdk's). Entry into mitosis requires phosphorylation of many proteins targeted by mitotic Cdk, and exit from mitosis requires proteolysis of mitotic cyclins and dephosphorylation of their targeted proteins. Mitotic exit in budding yeast is known to involve the interplay of mitotic kinases (Cdk and Polo kinases) and phosphatases (Cdc55/PP2A and Cdc14), as well as the action of the anaphase promoting complex (APC) in degrading specific proteins in anaphase and telophase. To understand the intricacies of this mechanism, we propose a mathematical model for the molecular events during mitotic exit in budding yeast. The model captures the dynamics of this network in wild-type yeast cells and 110 mutant strains. The model clarifies the roles of Polo-like kinase (Cdc5) in the Cdc14 early anaphase release pathway and in the G-protein regulated mitotic exit network.

Show MeSH
Related in: MedlinePlus