An Application of Invertibility of Boolean Control Networks to the Control of the Mammalian Cell Cycle.

Abstract

In Fauré etal. (2006), the dynamics of the core network regulating the mammalian cell cycle is formulated as a Boolean control network (BCN) model consisting of nine proteins as state nodes and a tenth protein (protein CycD) as the control input node. In this model, one of the state nodes, protein Cdc20, plays a central role in the separation of sister chromatids. Hence, if any Cdc20 sequence can be obtained, fully controlling the mammalian cell cycle is feasible. Motivated by this fact, we study whether any Cdc20 sequence can be obtained theoretically. We formulate the foregoing problem as the invertibility of BCNs, that is, whether one can obtain any Cdc20 sequence by designing input (i.e., protein CycD) sequences. We give an algorithm to verify the invertibility of any BCN, and find that the BCN model for the core network regulating the mammalian cell cycle is not invertible, that is, one cannot obtain any Cdc20 sequence. We further present another algorithm to test whether a finite Cdc20 sequence can be generated by the BCN model, which leads to a series of periodic infinite Cdc20 sequences with alternately active and inactive Cdc20 segments. States of these sequences are alternated between the two attractors in the proposed model, which reproduces correctly how a cell exits the cell cycle to enter the quiescent state, or the opposite.