Figure 1.
Schematic of the models for (a) the circadian clock and (b) the cell cycle in mammalian cells. In (a), the circadian clock network (in orange) involves the negative autoregulation of the Per and Cry genes, via the inhibition of the activators BMAL1 and CLOCK by the PER and CRY proteins. An additional negative feedback on Bmal1 expression is mediated by the REV-ERBα protein, which is itself induced by CLOCK/BMAL1. These feedback regulations are responsible for the onset of circadian oscillations in the network (see [20–22] for reviews, and [24] for further details on the model). The cell cycle controls the circadian clock through several interactions, only one of which is shown: the phosphorylation by CDK1 (of maximum rate VCdk1) of REV-ERBα, which enhances the degradation of this protein. In (b), the CDK network (in blue) that governs the dynamics of the mammalian cell cycle consists of four CDK modules, centred on the complexes Cyclin D/CDK4–6, Cyclin E/CDK2, Cyclin A/CDK2 and Cyclin B/CDK1, which control, respectively, the progression along the G1, S and G2 phases and the G2/M transition [23], as shown on the right part of (b). Also shown in this scheme are some of the important protein factors involved in regulation of the CDK network: growth factors (GF), the retinoblastoma protein, non-phosphorylated (pRB) or inactivated through one (pRBp) or multiple phosphorylations (pRBpp) by CDK1 and CDK2 (a, active; i, inactive); the transcription factor E2F; the CDK inhibitor p21; the proteins Cdh1, Skp2 and CDC20 involved in cyclin degradation; and the kinase WEE1, which inhibits CDK1. Only some of the main regulatory interactions are shown in this simplified scheme. The regulatory design of the CDK network is such that each CDK module activates the next module and inhibits the previous one. Such a regulation results in the repetitive, ordered, transient activation of the four CDK modules that control the successive phases of the cell cycle. The circadian clock controls the cell cycle through several interactions, only one of which is shown: the induction by BMAL1 of the expression (at a rate vsw) of the gene Wee1, which codes for the inhibitory kinase WEE1. The models for the cell cycle and circadian clock contain 41 and 19 variables, respectively. The models for the circadian clock and the cell cycle are described in more detail in [24] and [25], respectively. (Online version in colour.)