Testing a Mathematical Model of the Yeast Cell Cycle

Abstract

We derived novel, testable predictions from a mathematical model of the budding yeast cell cycle. A key qualitative prediction of bistability was confirmed in a strain simultaneously lacking cdc14 and G1 cyclins. The model correctly predicted quantitative dependence of cell size on gene dosage of the G1 cyclin CLN3, but it incorrectly predicted strong genetic interactions between G1 cyclins and the anaphase-promoting complex specificity factor Cdh1. To provide constraints on model generation, we determined accurate concentrations for the abundance of all nine cyclins as well as the inhibitor Sic1 and the catalytic subunit Cdc28. For many of these we determined abundance throughout the cell cycle by centrifugal elutriation, in the presence or absence of Cdh1. In addition, perturbations to the Clb-kinase oscillator were introduced, and the effects on cyclin and Sic1 levels were compared between model and experiment. Reasonable agreement was obtained in many of these experiments, but significant experimental discrepancies from the model predictions were also observed. Thus, the model is a strong but incomplete attempt at a realistic representation of cell cycle control. Constraints of the sort developed here will be important in development of a truly predictive model.

Mathematical modeling as a tool for investigating cell cycle control networks

“…For example, a comprehensive mathematical model of the cell cycle control network in Saccharomyces cerevisiae describes the behavior of more than 100 genetic mutants (4,22). Rigorous tests of the model have been performed by creating new mutants predicted by the model to give the most informative phenotypes (23) and by challenging the model to predict phenotypes of yet unpublished mutants (24). Complete details of the model are available at an easily navigable web site: http://mpf.biol.vt.edu/research/budding_yeast_model/pp/.…”

Hysteresis drives cell-cycle transitions in Xenopus laevis egg extracts

“…Bistability has been observed in the budding yeast cell cycle where, under identical culture conditions, a cell may arrest stably in either G 1 phase (low Cdk1 activity) or S͞G 2 ͞M phase (high Cdk1 activity), depending on how the culture is prepared (26). In this study, we demonstrate bistability and hysteresis in frog egg extracts, suggesting that these dynamical properties of the Cdk control system may indeed be common regulatory features of eukaryotic cell cycles, as predicted (17,(20)(21)(22)(23).…”

Biological switches and clocks

“…The molecular machinery controlling cell growth and division in yeast cells, embryos and mammalian somatic cells received a great deal of attention from molecular biologists in the 1990s, with a few theoretical groups trying to keep pace with the flood of genetic and biochemical data (Obeyesekere et al 1996;Kohn 1998;Aguda & Tang 1999;Chen et al 2000;Qu et al 2004). Although the experimentalists paid little attention to modellers during this time, in recent years there have appeared many influential papers that self-consciously test (and confirm) predictions of the models (Cross et al 2002(Cross et al , 2005Cross 2003;Pomerening et al 2003;Sha et al 2003) or bring modelling to bear on experimental design and interpretation (Pomerening et al 2005;Queralt et al 2006). All eukaryotes use the same basic mechanism, based on cyclin-dependent kinases, to regulate the progression of DNA synthesis, mitosis and cell division (Csikasz-Nagy et al 2006), but the idiosyncrasies of specific cell types require specifically tailored mathematical models (Chen et al 2004;Calzone et al 2007).…”