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Cell size at S phase initiation: an emergent property of the G1/S network.

Barberis M, Klipp E, Vanoni M, Alberghina L - PLoS Comput. Biol. (2007)

Bottom Line: The model was tested by simulation in several genetic and nutritional setups and was found to be neatly consistent with experimental data.To estimate PS, the authors developed a hybrid model including a probabilistic component for firing of DNA replication origins.Sensitivity analysis of PS provides a novel relevant conclusion: PS is an emergent property of the G1 to S network that strongly depends on growth rate.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.

ABSTRACT
The eukaryotic cell cycle is the repeated sequence of events that enable the division of a cell into two daughter cells. It is divided into four phases: G1, S, G2, and M. Passage through the cell cycle is strictly regulated by a molecular interaction network, which involves the periodic synthesis and destruction of cyclins that bind and activate cyclin-dependent kinases that are present in nonlimiting amounts. Cyclin-dependent kinase inhibitors contribute to cell cycle control. Budding yeast is an established model organism for cell cycle studies, and several mathematical models have been proposed for its cell cycle. An area of major relevance in cell cycle control is the G1 to S transition. In any given growth condition, it is characterized by the requirement of a specific, critical cell size, PS, to enter S phase. The molecular basis of this control is still under discussion. The authors report a mathematical model of the G1 to S network that newly takes into account nucleo/cytoplasmic localization, the role of the cyclin-dependent kinase Sic1 in facilitating nuclear import of its cognate Cdk1-Clb5, Whi5 control, and carbon source regulation of Sic1 and Sic1-containing complexes. The model was implemented by a set of ordinary differential equations that describe the temporal change of the concentration of the involved proteins and protein complexes. The model was tested by simulation in several genetic and nutritional setups and was found to be neatly consistent with experimental data. To estimate PS, the authors developed a hybrid model including a probabilistic component for firing of DNA replication origins. Sensitivity analysis of PS provides a novel relevant conclusion: PS is an emergent property of the G1 to S network that strongly depends on growth rate.

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Population Effects on Budding Onset in Yeast Populations Grown in Glucose or in EthanolTo mimic differences in individual cells in a population, all parameter values are drawn from a normal distribution having the values of the ODE model as mean value.(A,D) A series of individual realizations is shown for Cdk1-Cln1,2cyt. The white curves represent the realizations for the original parameters.(B,E) Individual realizations for Cdk1-Clb5,6nuc.(C,F) Cumulative number (in %) of budded cells as a function of simulation time determined from the realizations presented in (A) and (D) (see Materials and Methods for details on calculation on budding time). Black dots refer to the experimental budding points determined for elutriated wild-type cells.
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pcbi-0030064-g007: Population Effects on Budding Onset in Yeast Populations Grown in Glucose or in EthanolTo mimic differences in individual cells in a population, all parameter values are drawn from a normal distribution having the values of the ODE model as mean value.(A,D) A series of individual realizations is shown for Cdk1-Cln1,2cyt. The white curves represent the realizations for the original parameters.(B,E) Individual realizations for Cdk1-Clb5,6nuc.(C,F) Cumulative number (in %) of budded cells as a function of simulation time determined from the realizations presented in (A) and (D) (see Materials and Methods for details on calculation on budding time). Black dots refer to the experimental budding points determined for elutriated wild-type cells.

Mentions: All data presented above refer to simulation of an idealized single cell. By taking into account biological variability, it is possible to simulate a cohort of synchronous cells that more closely resembles, for instance, a population of newborn elutriated cells placed to grow in a fresh medium. To this end, we modeled a population by a probabilistic approach that simulates cell-to-cell variability through repeated simulations with noisy parameters (see Materials and Methods for further details) (i.e., all parameters were sampled from a normal distribution with the original model values [Tables 2 and 3] as mean value). Figure 7 shows representative time courses for the Cdk1-Cln1,2cyt and Cdk1-Clb5,6nuc complexes for cells growing in glucose (Figure 7A and 7B) and in ethanol media (Figure 7D and 7E). The simulated time course of budding obtained for a population growing in glucose (black dots) is very closed to the experimentally observed one (gray curve), both in the time required for the onset of budding and in the initial slope (Figure 7C). The same simulation run for ethanol-grown cells (Figure 7F) indicates a close agreement in the timing of the onset of budding and a satisfactory slope for three subsequent points. Although the maximum value of experimental budding is not reached in both simulations, we observe a fairly good correspondence between experimental and simulated behaviors. Taken together, these data show that the model correctly predicts properties of the cells related to the G1 to S transition that have not been taken into account during model construction, thereby offering support to the overall consistency between input data and output performance.


Cell size at S phase initiation: an emergent property of the G1/S network.

Barberis M, Klipp E, Vanoni M, Alberghina L - PLoS Comput. Biol. (2007)

Population Effects on Budding Onset in Yeast Populations Grown in Glucose or in EthanolTo mimic differences in individual cells in a population, all parameter values are drawn from a normal distribution having the values of the ODE model as mean value.(A,D) A series of individual realizations is shown for Cdk1-Cln1,2cyt. The white curves represent the realizations for the original parameters.(B,E) Individual realizations for Cdk1-Clb5,6nuc.(C,F) Cumulative number (in %) of budded cells as a function of simulation time determined from the realizations presented in (A) and (D) (see Materials and Methods for details on calculation on budding time). Black dots refer to the experimental budding points determined for elutriated wild-type cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1851985&req=5

pcbi-0030064-g007: Population Effects on Budding Onset in Yeast Populations Grown in Glucose or in EthanolTo mimic differences in individual cells in a population, all parameter values are drawn from a normal distribution having the values of the ODE model as mean value.(A,D) A series of individual realizations is shown for Cdk1-Cln1,2cyt. The white curves represent the realizations for the original parameters.(B,E) Individual realizations for Cdk1-Clb5,6nuc.(C,F) Cumulative number (in %) of budded cells as a function of simulation time determined from the realizations presented in (A) and (D) (see Materials and Methods for details on calculation on budding time). Black dots refer to the experimental budding points determined for elutriated wild-type cells.
Mentions: All data presented above refer to simulation of an idealized single cell. By taking into account biological variability, it is possible to simulate a cohort of synchronous cells that more closely resembles, for instance, a population of newborn elutriated cells placed to grow in a fresh medium. To this end, we modeled a population by a probabilistic approach that simulates cell-to-cell variability through repeated simulations with noisy parameters (see Materials and Methods for further details) (i.e., all parameters were sampled from a normal distribution with the original model values [Tables 2 and 3] as mean value). Figure 7 shows representative time courses for the Cdk1-Cln1,2cyt and Cdk1-Clb5,6nuc complexes for cells growing in glucose (Figure 7A and 7B) and in ethanol media (Figure 7D and 7E). The simulated time course of budding obtained for a population growing in glucose (black dots) is very closed to the experimentally observed one (gray curve), both in the time required for the onset of budding and in the initial slope (Figure 7C). The same simulation run for ethanol-grown cells (Figure 7F) indicates a close agreement in the timing of the onset of budding and a satisfactory slope for three subsequent points. Although the maximum value of experimental budding is not reached in both simulations, we observe a fairly good correspondence between experimental and simulated behaviors. Taken together, these data show that the model correctly predicts properties of the cells related to the G1 to S transition that have not been taken into account during model construction, thereby offering support to the overall consistency between input data and output performance.

Bottom Line: The model was tested by simulation in several genetic and nutritional setups and was found to be neatly consistent with experimental data.To estimate PS, the authors developed a hybrid model including a probabilistic component for firing of DNA replication origins.Sensitivity analysis of PS provides a novel relevant conclusion: PS is an emergent property of the G1 to S network that strongly depends on growth rate.

View Article: PubMed Central - PubMed

Affiliation: Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy.

ABSTRACT
The eukaryotic cell cycle is the repeated sequence of events that enable the division of a cell into two daughter cells. It is divided into four phases: G1, S, G2, and M. Passage through the cell cycle is strictly regulated by a molecular interaction network, which involves the periodic synthesis and destruction of cyclins that bind and activate cyclin-dependent kinases that are present in nonlimiting amounts. Cyclin-dependent kinase inhibitors contribute to cell cycle control. Budding yeast is an established model organism for cell cycle studies, and several mathematical models have been proposed for its cell cycle. An area of major relevance in cell cycle control is the G1 to S transition. In any given growth condition, it is characterized by the requirement of a specific, critical cell size, PS, to enter S phase. The molecular basis of this control is still under discussion. The authors report a mathematical model of the G1 to S network that newly takes into account nucleo/cytoplasmic localization, the role of the cyclin-dependent kinase Sic1 in facilitating nuclear import of its cognate Cdk1-Clb5, Whi5 control, and carbon source regulation of Sic1 and Sic1-containing complexes. The model was implemented by a set of ordinary differential equations that describe the temporal change of the concentration of the involved proteins and protein complexes. The model was tested by simulation in several genetic and nutritional setups and was found to be neatly consistent with experimental data. To estimate PS, the authors developed a hybrid model including a probabilistic component for firing of DNA replication origins. Sensitivity analysis of PS provides a novel relevant conclusion: PS is an emergent property of the G1 to S network that strongly depends on growth rate.

Show MeSH
Related in: MedlinePlus