Cell cycle regulation by feed-forward loops coupling transcription and phosphorylation.
Csikász-Nagy A., Kapuy O., Tóth A., Pál C., Jensen LJ., Uhlmann F., Tyson JJ., Novák B.
The eukaryotic cell cycle requires precise temporal coordination of the activities of hundreds of 'executor' proteins (EPs) involved in cell growth and division. Cyclin-dependent protein kinases (Cdks) play central roles in regulating the production, activation, inactivation and destruction of these EPs. From genome-scale data sets of budding yeast, we identify 126 EPs that are regulated by Cdk1 both through direct phosphorylation of the EP and through phosphorylation of the transcription factors that control expression of the EP, so that each of these EPs is regulated by a feed-forward loop (FFL) from Cdk1. By mathematical modelling, we show that such FFLs can activate EPs at different phases of the cell cycle depending of the effective signs (+ or -) of the regulatory steps of the FFL. We provide several case studies of EPs that are controlled by FFLs exactly as our models predict. The signal-transduction properties of FFLs allow one (or a few) Cdk signal(s) to drive a host of cell cycle responses in correct temporal sequence.