Start and the restriction point

Abstract

Commitment to division requires that cells sense, interpret, and respond appropriately to multiple signals. In most eukaryotes, cells commit to division in G1 before DNA replication. Beyond a point, known as Start in yeast and the restriction point in mammals, cells will proceed through the cell cycle despite changes in upstream signals. In metazoans, misregulated G1 control can lead to developmental problems or disease, so it is important to understand how cells decipher the myriad external and internal signals that contribute to the fundamental all-or-none decision to divide. Extensive study of G1 control in the budding yeast Saccharomyces cerevisiae and mammalian culture systems has revealed highly similar networks regulating commitment. However, protein sequences of functional orthologs often indicate a total lack of conservation suggesting significant evolution of G1 control. Here, we review recent studies defining the conserved and diverged features of G1 control and highlight systems-level aspects that may be common to other biological regulatory networks.

Figure 1

Despite a lack of sequence homology, G1 control networks are similar in both yeast (left panel) and mammals (right panel). Proteins and signals with similar functions are similarly shaped/colored. Upstream growth cues activate G1 cyclins, which drive progression into S phase via the activation of a positive feedback loop. Differentiation signals, including the pheromone-activated MAPK pathway in yeast, activate proteins that inhibit cyclin-CDK activity, leading to the increased stability of a low CDK activity cellular state.

Figure 2

A. Simplified scheme of the decision-making yeast network regulating Start. B. Increased duration of α-factor exposure leads to the accumulation of Far1, which increases the amount of cyclin-CDK required to drive yeast into the cell cycle. Increasing Far1 reflects the corresponding temporal integration of pheromone pathway activity. C. Cell cycle commitment is a bistable process. Once a threshold level of cyclin-CDK is reached, cells rapidly transition to the committed state. The black arrows illustrate one potential path. The dotted line represents an unstable intermediate state. Increased Far1 concentrations favor the low SBF activity state and shift the curve toward the right indicating that higher cyclin-CDK concentrations are required to commit a cell to division.

Figure 3

General experimental scheme for using time-lapse imaging, fluorescent reporters, and microfluidics to analyze commitment within a predictive framework. For pathways that employ irreversible transitions, following a cell before and after the transition allows the determination of molecular events committing a cell to a downstream fate if a threshold can be determined using a fluorescent reporter (see text).