Entrainment of the Mammalian Cell Cycle by the Circadian Clock: Modeling Two Coupled Cellular Rhythms
Figure 2
Entrainment of the cell cycle by the circadian clock through the kinase Wee1.
The time series show the evolution of cyclin B/Cdk1 (red), the kinase Wee1 (blue), and the circadian complex CLOCK-BMAL1 (green) in the absence (A, B) or presence (C, D) of coupling to the circadian clock. The autonomous period of the cell cycle is either smaller (left column) or larger (right column) than 24 h; prior to coupling (upper row), the oscillations in the cell cycle (reflected by Wee1 and cyclin B/Cdk1) have then a period distinct from that of the circadian clock (reflected by CLOCK-BMAL1). In both cases the coupling to the circadian clock via Wee1 (see Methods) results in the entrainment of the cell cycle (lower row): the period then shifts from 20 h (A) to 24 h (C), and from 28 h (B) to 24 h (D), so that now Wee1, cyclin B/Cdk1 and CLOCK-BMAL1 all oscillate with a fixed phase relationship and with the same period equal to 24 h. The curves have been obtained by numerical integration of the kinetic equations [1]–[39] listed in the Supporting Information in Ref. 14, supplemented with eqs. [1]–[2] given in Methods. The latter equations include the variable CLOCK-BMAL1 whose time evolution is obtained by the concomitant numerical integration of eqs. [1]–[19] that govern the dynamics of the model for the mammalian circadian clock [21]; these equations are listed together with parameter values in the Supporting Information in Ref. 21 (see Methods). Parameter values for the Cdk network are those listed in Table S2 of [14], with vcb = 0.055 µM h−1. Moreover, vsw = 0 for A and B, and 0.1 µM h−1 for C and D; Kaw = 2 nM, Vdmw = 0.5 µM h−1, Kdmw = 0.5 µM, nmw = 4, and ksw = 5 h−1.