Modeling the septation initiation network (SIN) in fission yeast cells

Abstract

Cytokinesis in fission yeast is controlled by a signal transduction pathway called the Septation Initiation Network (SIN). From a dynamical point of view the most interesting questions about the regulation of fission yeast cytokinesis are: how do wild type cells ensure that septation is initiated only once per cycle? Why does the control system stay in a continuously septating state in some mutant strains? And how is it that the SIN remains active when cytokinesis fails? To answer these questions we construct a simplified mathematical model of the SIN and graft this regulatory module onto our previous model of cyclin-dependent kinase (Cdk) dynamics in fission yeast cells. The SIN is both activated and inhibited by mitotic Cdk/cyclin complexes. As a consequence of this dual regulation, the SIN gets activated only once at the end of mitosis, when Cdk activity drops. The mathematical model describes the timing of septation not only in wild type cells but also in mutants where components of the SIN are knocked out. The model predicts phenotypes of some uncharacterized mutant cells and shows how a cytokinesis checkpoint can stop the cell cycle if septation fails.

Linkers of Cell Polarity and Cell Cycle Regulation in the Fission Yeast Protein Interaction Network

“…Daughter cells resume their cyclic pattern of growth at the ends and division at the middle, a pattern that relies on the cytoskeleton of actin and microtubules and on diverse polarity-regulating proteins (‘polarity factors’). Cytokinesis, polarity, and the cell cycle have been extensively studied in fission yeast –using both experiments and mathematical modelling [14]–[18]. The insights gained from studies in fission yeast often carry over to higher eukaryotes, as the molecular machinery controlling those processes has been highly conserved throughout evolution [1], [19], [20].…”

On the Role of Cell Signaling Models in Cancer Research

“…Instead, certain ingredients are included to ensure that, as simply as possible, the model reproduces what are believed to be fundamental properties of the system studied. Interestingly, and although phenomenological descriptions have proven their utility in many contexts (6–8), if the observer is not aware of some of the critical properties of the system, these could be easily left out of the description and perhaps major and important behaviors of the system would not be predicted. Simplified model approaches could very well succeed in providing both explanatory and predictive tools, provided that they capture the much-sought-after essential underlying mechanisms of the system being considered.…”

Transcriptional Regulation Is a Major Controller of Cell Cycle Transition Dynamics

“…Cdc14 inhibits the transition inhibitor Pds1 and activates the transition activators Sic1 and Cdh1 and periodically appearing Cdc28/Clb2 acts as an inhibitor of the transition – leading to a GO transcriptional control. Cdc28/Clb2 also affects Cdc14 activity directly [44], the introduction of such crosstalk do not influence our simulation results (not shown), still such feed-forward regulation could help the irreversibility of the transition [45], [46].…”