Entrainment of the Mammalian Cell Cycle by the Circadian Clock: Modeling Two Coupled Cellular Rhythms
Figure 12
Circadian entrainment of a quiescent cell.
(A) Upon raising the rate of pRB synthesis, vspRB, above a critical value, and in the absence of coupling to the circadian clock (0<t<120 h) the Cdk network reaches a stable steady state associated with quiescence [14]. Coupling to the circadian clock through Wee1 is achieved by raising the rate of synthesis of Wee1 mRNA, vsw, from 0 to 0.1 µM h−1 in t = 120 h (vertical arrow); this results in the entrainment of the Cdk network, reflected by the circadian variation of cyclin B/Cdk1 (red). (B) Further increase in the rate of synthesis of pRB still yields a stable steady state, but entrainment by the circadian clock fails to occur, as only tiny variations in the level of cyclin B/Cdk1 are observed. (C) Instead of increasing pRB, we increase the level of the phosphatase Cdc25 acting on Cdk1. The Cdk network then reaches a stable steady state characterized by a high level of cyclin B/Cdk1 [14]. Circadian entrainment of Cdk1 through the circadian variation in Wee1 (blue) is also obtained in such conditions. Parameter vspRB, which is equal to 0.8 µM h−1 in Figs. 2–11, is raised up to 1 µM h−1 in (A) and 2 µM h−1 in (B). In (C), the rate of synthesis of Cdc25, vspbi, which is equal to 0.12 µM h−1 in all other figures, is raised to 0.3 µM h−1, with vspRB = 0.8 µM h−1. Other parameters are in Fig. 4A.