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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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Simulation of mitotic progression of cells containing overexpressed CDC5 and inactive cdc5 mutations.(A) Cdc5 is necessary for ME. Cdc20 block-and-release was simulated as in Figure 2 with inactive Cdc5 (cdc5-as1; effpol = 0). Cdc14 is not released, nor is Cdh1 activated. (B) The MEN requirement for ME can be bypassed by overexpressed Cdc5. Cdc20 block-and-release was simulated as usual, with inactive Cdc15 (cdc15-2; effc15 = 0) and with Cdc5 overexpressed 30-fold (GAL-CDC5; ks,polo = 0.3). (C) Overexpressed Cdc5 is sufficient for Cdc14 release when FEAR and MEN are inactive. Simulation was started in an arrested steady state with initial conditions of Clb2 and Polo were set less than metaphase values to represent an earlier stage of the arrest by hydroxyurea (Clb2 = 0.8, Polo = 0.6, Poloi = 0.2, ks,b2 = 0.024, ks,polo = 0.006) and with inactive Cdc15 (effc15 = 0) for 15 min. Then Cdc5 and Pds1 overexpressions were induced at time zero (ks,polo = 0.3, ks,pds = 0.45, kd,pds′ = 0). (D) The Cdc5 requirement for Cdc14 release and ME can be bypassed by overexpression of a truncated version of Cdc15. Cdc20 block-and-release was pre-simulated for 60 min with no synthesis of either Cdc20 or Cdc5 (ks,polo = ks,20 = 0; setting also the initial conditions for Cdc5 active and inactive forms to zero) while the total concentration of Cdc15 was increased 20-fold and inhibition of Cdc15 by Cdk was reduced 1000-fold (ki,c15′ = 0.00009, CDC15T = 20). At t = 0, Cdc20 synthesis is induced as usual (ks,20 = 0.015). (E) Cdc14 is not released in cdc5-1 and cdc5-1 cdc14-1 cells in E and F. Therefore, Cdc14 release in the cdc14-1 mutant may be attributable solely to Net1 phosphorylation by Cdc5. Simulation in E was done similar to Figure 4A except that effpol was set to 0.1 for the small residual activity of Cdc5. (F) Simulation in F was done similar to A except that activity of Cdc14 was set to zero (effc14 = 0).
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pone-0030810-g004: Simulation of mitotic progression of cells containing overexpressed CDC5 and inactive cdc5 mutations.(A) Cdc5 is necessary for ME. Cdc20 block-and-release was simulated as in Figure 2 with inactive Cdc5 (cdc5-as1; effpol = 0). Cdc14 is not released, nor is Cdh1 activated. (B) The MEN requirement for ME can be bypassed by overexpressed Cdc5. Cdc20 block-and-release was simulated as usual, with inactive Cdc15 (cdc15-2; effc15 = 0) and with Cdc5 overexpressed 30-fold (GAL-CDC5; ks,polo = 0.3). (C) Overexpressed Cdc5 is sufficient for Cdc14 release when FEAR and MEN are inactive. Simulation was started in an arrested steady state with initial conditions of Clb2 and Polo were set less than metaphase values to represent an earlier stage of the arrest by hydroxyurea (Clb2 = 0.8, Polo = 0.6, Poloi = 0.2, ks,b2 = 0.024, ks,polo = 0.006) and with inactive Cdc15 (effc15 = 0) for 15 min. Then Cdc5 and Pds1 overexpressions were induced at time zero (ks,polo = 0.3, ks,pds = 0.45, kd,pds′ = 0). (D) The Cdc5 requirement for Cdc14 release and ME can be bypassed by overexpression of a truncated version of Cdc15. Cdc20 block-and-release was pre-simulated for 60 min with no synthesis of either Cdc20 or Cdc5 (ks,polo = ks,20 = 0; setting also the initial conditions for Cdc5 active and inactive forms to zero) while the total concentration of Cdc15 was increased 20-fold and inhibition of Cdc15 by Cdk was reduced 1000-fold (ki,c15′ = 0.00009, CDC15T = 20). At t = 0, Cdc20 synthesis is induced as usual (ks,20 = 0.015). (E) Cdc14 is not released in cdc5-1 and cdc5-1 cdc14-1 cells in E and F. Therefore, Cdc14 release in the cdc14-1 mutant may be attributable solely to Net1 phosphorylation by Cdc5. Simulation in E was done similar to Figure 4A except that effpol was set to 0.1 for the small residual activity of Cdc5. (F) Simulation in F was done similar to A except that activity of Cdc14 was set to zero (effc14 = 0).

Mentions: For all our model simulations, we indicate the figure presenting the particular model simulation, such as “simulated in Figure 4D”, and the paper presenting the simulated experiment(s), with a literature citation. If any statement in the paper does not include “simulated in Figure number”, then it is either our proposal or claim (if no reference is given) or an experimental finding (if a reference is given).


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

Hancioglu B, Tyson JJ - PLoS ONE (2012)

Simulation of mitotic progression of cells containing overexpressed CDC5 and inactive cdc5 mutations.(A) Cdc5 is necessary for ME. Cdc20 block-and-release was simulated as in Figure 2 with inactive Cdc5 (cdc5-as1; effpol = 0). Cdc14 is not released, nor is Cdh1 activated. (B) The MEN requirement for ME can be bypassed by overexpressed Cdc5. Cdc20 block-and-release was simulated as usual, with inactive Cdc15 (cdc15-2; effc15 = 0) and with Cdc5 overexpressed 30-fold (GAL-CDC5; ks,polo = 0.3). (C) Overexpressed Cdc5 is sufficient for Cdc14 release when FEAR and MEN are inactive. Simulation was started in an arrested steady state with initial conditions of Clb2 and Polo were set less than metaphase values to represent an earlier stage of the arrest by hydroxyurea (Clb2 = 0.8, Polo = 0.6, Poloi = 0.2, ks,b2 = 0.024, ks,polo = 0.006) and with inactive Cdc15 (effc15 = 0) for 15 min. Then Cdc5 and Pds1 overexpressions were induced at time zero (ks,polo = 0.3, ks,pds = 0.45, kd,pds′ = 0). (D) The Cdc5 requirement for Cdc14 release and ME can be bypassed by overexpression of a truncated version of Cdc15. Cdc20 block-and-release was pre-simulated for 60 min with no synthesis of either Cdc20 or Cdc5 (ks,polo = ks,20 = 0; setting also the initial conditions for Cdc5 active and inactive forms to zero) while the total concentration of Cdc15 was increased 20-fold and inhibition of Cdc15 by Cdk was reduced 1000-fold (ki,c15′ = 0.00009, CDC15T = 20). At t = 0, Cdc20 synthesis is induced as usual (ks,20 = 0.015). (E) Cdc14 is not released in cdc5-1 and cdc5-1 cdc14-1 cells in E and F. Therefore, Cdc14 release in the cdc14-1 mutant may be attributable solely to Net1 phosphorylation by Cdc5. Simulation in E was done similar to Figure 4A except that effpol was set to 0.1 for the small residual activity of Cdc5. (F) Simulation in F was done similar to A except that activity of Cdc14 was set to zero (effc14 = 0).
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pone-0030810-g004: Simulation of mitotic progression of cells containing overexpressed CDC5 and inactive cdc5 mutations.(A) Cdc5 is necessary for ME. Cdc20 block-and-release was simulated as in Figure 2 with inactive Cdc5 (cdc5-as1; effpol = 0). Cdc14 is not released, nor is Cdh1 activated. (B) The MEN requirement for ME can be bypassed by overexpressed Cdc5. Cdc20 block-and-release was simulated as usual, with inactive Cdc15 (cdc15-2; effc15 = 0) and with Cdc5 overexpressed 30-fold (GAL-CDC5; ks,polo = 0.3). (C) Overexpressed Cdc5 is sufficient for Cdc14 release when FEAR and MEN are inactive. Simulation was started in an arrested steady state with initial conditions of Clb2 and Polo were set less than metaphase values to represent an earlier stage of the arrest by hydroxyurea (Clb2 = 0.8, Polo = 0.6, Poloi = 0.2, ks,b2 = 0.024, ks,polo = 0.006) and with inactive Cdc15 (effc15 = 0) for 15 min. Then Cdc5 and Pds1 overexpressions were induced at time zero (ks,polo = 0.3, ks,pds = 0.45, kd,pds′ = 0). (D) The Cdc5 requirement for Cdc14 release and ME can be bypassed by overexpression of a truncated version of Cdc15. Cdc20 block-and-release was pre-simulated for 60 min with no synthesis of either Cdc20 or Cdc5 (ks,polo = ks,20 = 0; setting also the initial conditions for Cdc5 active and inactive forms to zero) while the total concentration of Cdc15 was increased 20-fold and inhibition of Cdc15 by Cdk was reduced 1000-fold (ki,c15′ = 0.00009, CDC15T = 20). At t = 0, Cdc20 synthesis is induced as usual (ks,20 = 0.015). (E) Cdc14 is not released in cdc5-1 and cdc5-1 cdc14-1 cells in E and F. Therefore, Cdc14 release in the cdc14-1 mutant may be attributable solely to Net1 phosphorylation by Cdc5. Simulation in E was done similar to Figure 4A except that effpol was set to 0.1 for the small residual activity of Cdc5. (F) Simulation in F was done similar to A except that activity of Cdc14 was set to zero (effc14 = 0).
Mentions: For all our model simulations, we indicate the figure presenting the particular model simulation, such as “simulated in Figure 4D”, and the paper presenting the simulated experiment(s), with a literature citation. If any statement in the paper does not include “simulated in Figure number”, then it is either our proposal or claim (if no reference is given) or an experimental finding (if a reference is given).

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