Abstract
We perform logic-based network analysis on a model of the mammalian cell cycle. This model is composed of a Restriction Switch driving cell cycle commitment and a Phase Switch driving mitotic entry and exit. By generalizing the concept of stable motif, i.e., a self-sustaining positive feedback loop that maintains an associated state, we introduce the concept of a conditionally stable motif, the stability of which is contingent on external conditions. We show that the stable motifs of the Phase Switch are contingent on the state of three nodes through which it receives input from the rest of the network. Biologically, these conditions correspond to cell cycle checkpoints. Holding these nodes locked (akin to a checkpoint-free cell) transforms the Phase Switch into an autonomous oscillator that robustly toggles through the cell cycle phases G1, G2 and mitosis. The conditionally stable motifs of the Phase Switch Oscillator are organized into an ordered sequence, such that they serially stabilize each other but also cause their own destabilization. Along the way they channel the dynamics of the module onto a narrow path in state space, lending robustness to the oscillation. Self-destabilizing conditionally stable motifs suggest a general negative feedback mechanism leading to sustained oscillations.
Highlights
We perform logic-based network analysis on a model of the mammalian cell cycle
In particular, assume that the essential logic by which regulatory interactions drive cell behavior can be adequately described by a network of molecular components, where the activity of each is described by a binary variable
Deritei et al argued in 2016 that cellular regulatory networks exhibit dynamical modularity[17]: they are composed of a hierarchy of coupled modules, each of which is responsible for a discrete set of mutually exclusive phenotypic outcomes, such as survival vs. apoptosis, cell cycle progression vs. cell cycle arrest
Summary
We perform logic-based network analysis on a model of the mammalian cell cycle. This model is composed of a Restriction Switch driving cell cycle commitment and a Phase Switch driving mitotic entry and exit. We show that the stable motifs of the Phase Switch are contingent on the state of three nodes through which it receives input from the rest of the network These conditions correspond to cell cycle checkpoints. An especially important, yet challenging goal is to identify the repertoire of cellular phenotypes (e.g. cell cycle progression, cell cycle arrest, programmed cell death) and the decisions or trajectories that lead to each phenotype Dynamic models represent such phenotypes as attractors (e.g. steady states or sustained oscillations). Deritei et al argued in 2016 that cellular regulatory networks exhibit dynamical modularity[17]: they are composed of a hierarchy of coupled modules, each of which is responsible for a discrete set of mutually exclusive phenotypic outcomes, such as survival vs apoptosis (programmed cell death), cell cycle progression vs cell cycle arrest. A significantly larger five-module Boolean model of cell cycle coordination with growth factor signaling shows modular dynamics[19]
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