Budding yeast cell cycle (Fauré et al. 2009)

Leaning on former models, we have defined a logical model for three regulatory modules involved in the control of the mitotic cell cycle in budding yeast, namely the core cell cycle module, the morphogenetic checkpoint, and a module controlling the exit from mitosis. Consistency with available data has been assessed through a systematic analysis of model behaviours for various genetic backgrounds and other perturbations. See:

• Logical modelling of the core engine
• Logical modelling of the budding yeast morphogenetic checkpoint
• Logical modelling of the budding yeast exit module

Here, we take advantage of compositional facilities of the logical formalism to combine these three models in order to generate a single comprehensive model involving over thirty regulatory components. The resulting logical model preserves all relevant characteristics of the original modules, while enabling the simulation of more sophisticated experiments (cf. [1]).

Chen et al (2004) [2] discussed the possibility to graft the model of the morphogenesis checkpoint published in a “companion study” by Ciliberto et al (2003) [3] to their model of the cell cycle, and to replace the hypothetical PPX by a more accurate version of the network controlling mitotic exit. We have adapted all three modules in the logical formalism, and coupled them together.

Coupling of the MCP module to the core cycling engine model

We have kept and left unchanged all components that were specific of the MCP module (Mih1, Swe1, Mpk1 and Hsl1), and similarly, all components specific of the core model. Among the components that were shared by both modules, MASS, MBF and the BUD received no input from the variables specific of the MCP, while their regulation amounted to a simplification of what had been proposed in the core cycling engine model. Hence, we kept these variables and their regulation from the core model and left them unchanged in the coupled model. In contrast, in the coupled model, CycB get inputs from components specific of each of the two modules. Moreover, in the MCP module, CycB is Boolean, whereas it is multilevel in the core model. Based on the parameters of CycB in each of the modules, we determined that CycB would have to satisfy the two sets of conditions to be active in the coupled model. Consequently, the logical formula giving the conditions of activation of CycB in the coupled model amounts to a logical AND between its formulas in the core cycling engine and in the MCP module. The main characteristics of the behaviour of the two original modules are conserved in the coupled model, in the case of the wild-type as for the different mutations simulated.

Coupling of the exit module to the core cycling engine model

The next step was to fuse the exit module to the core cycling engine. We followed the same method as with the coupling of the MCP. The first step was to identify which components and interactions were to be kept in the coupled model. Obviously, we chose to discard the hypothetical PPX, along with the parameters of the components of the exit network that were present in the core model (Net1, Cdc14, Tem1, Bub2-Bfa1, Cdc15 and Pds1), to replace them with their equivalents from the new exit module, including the SeparaseEsp1, PP2ACdc55 and Cdc5Polo that were not present in the core model. The logical rules for Clb2, Cdh1 and Cdc20 in the exit module amount to simplifications of their counterparts in the core model, so we kept the core model wiring and regulation in the coupled model for these components. Last but not least, we added regulation from Sic1 and Cdc6 towards Clb2 new targets to represent sequestration of the cyclins by the CKI (see the core cycling engine model for more details). The resulting model fits the more recent data used to built the exit module, and the behaviour of the core model is preserved. Still, one difficulty arose regarding mutant simulations for the exit module: the two mutants involving Cdk inhibition (see Queralt [i]et al.[/i], supplementary figure S6.4 [4]) could not be simulated in the coupled model, as inhibition of Cdk1 / Clb2 is the signal for cytokinesis in this model. This points out towards the “TARGET model” hypothesis discussed in Chen et al, where the trigger for cytokinesis would involve both a decrease of Cdk1 / Clb2 kinase activity and an increase in Cdc14 phosphatase activity.

References