Logical model specification aided by model-checking techniques: Application to the mammalian cell cycle regulation

Motivation: Understanding the temporal behaviour of biological regulatory networks requires the integration of molecular information into a formal model. However, the analysis of model dynamics faces a combinatorial explosion as the number of regulatory components and interactions increases. Results: We use model-checking techniques to verify sophisticated dynamical properties resulting from the model regulatory structure in the absence of kinetic assumption. We demonstrate the power of this approach by analysing a logical model of the molecular network controlling mammalian cell cycle. This approach enables a systematic analysis of model properties, the delineation of model limitations, and the assessment of various refinements and extensions based on recent experimental observations. The resulting logical model accounts for the main irreversible transitions between cell cycle phases, the sequential activation of cyclins, and the inhibitory role of Skp2, and further emphasizes the multifunctional role for the cell cycle inhibitor Rb. Availability and Implementation: The original and revised mammalian cell cycle models are available in the model repository associated with the public modelling software GINsim (http://ginsim.org/node/189).