Period control of the coupled clock and cell cycle systems

Abstract

The mammalian clock and cell cycle are two essential biological oscillators. In this work we investigate the coupling of these oscillators via non-linear dynamical modeling. We use previously developed reduced models of these systems and study a molecular interaction of MPF (mitosis promoting factor) repression by the CLOCK:BMAL1 protein complex, via induction of the repressor wee1. Furthermore, we propose an hypothesis whereby the clock responds to cell cycle Growth Factors (GFs) via a pathway involving the non-essential cell cycle complex cyclin D/cdk4 and study this interaction in the context of unidirectional clock → cell cycle coupling. We observe 1:1, 3:2, 4:3, 5:4 ratios of clock to cell cycle period and identify GF and the coupling strength c b as decisive control parameters for the system's state of synchronization. Synchronization ratios differing from 1:1, namely 3:2 and 5:4, have been observed in cells treated with the corticosteroid Dexamethasone (Dex). Here, we study Dex application and are able to reproduce the induction of ratios differing from 1:1. Finally, because slowing down the cell cycle is very relevant in the context of cancer therapies, we devise particular protocols of cell cycle period control with the use of clock inputs that are successful in substantially slowing down the cell cycle by the use of the system's synchronization dynamics, obtaining 2:3, 3:4, 4:5 ratios of clock to cell cycle period.

Control of synchronization ratios in clock/cell cycle coupling by growth factors and glucocorticoids

“…For instance, an immediate physiological benefit is to be able to control the period of one oscillator using inputs that affect the other. An example of this is provided by our previous work (Almeida et al [20]) where slowing down the cell cycle (which has implications for cancer control) was successfully achieved by tuning clock parameters. Moreover, there are already established compounds with a modulating effect on some of these parameters, such as GSk3β-inhibiting drugs, known to increase phosphorylation of REV-ERB, that can lead either to a decreased or increased clock period [27] depending on the GSK-inhibitor used [28,29].…”

“…In this work, we study the coupling of the mammalian cell cycle reduced model developed by Almeida et al [18] with the mammalian circadian clock model developed by Almeida et al [19] and investigate unidirectional cell cycle → clock coupling as well as bidirectional coupling. Recently, Almeida et al [20] have used the same models to study period control methods in unidirectional clock → cell cycle coupling via CLOCK : BMAL1 induction of wee1, an interaction we will also add to our system in §4.…”

Cell cycle period control through modulation of clock inputs

“…In Dex-treated cells a trimodal peak occurs for the distribution of mitosis with circadian clock phase 8 , an observation that has also been made by Nagoshi et al 11 . Our work is an extension of Almeida et al 12 and aims at exploring strategies of cell cycle period control in unidirectional clock → cell cycle coupling. For this, we use previously developed dynamical models of both systems (see Section 2).…”