(343e) Modeling the Influence of the HPA Axis and the Circadian Clock on the Regulation of the Cell Cycle

The circadian clock is a cell-autonomous, time-keeping system that orchestrates the activity of critical biological mechanisms enabling organisms to anticipate and adapt to fluctuating demands in response to a variety of environmental changes in a timely manner (1). The central circadian clock resides within the hypothalamic suprachiasmatic nucleus (SCN) and can be entrained by a number of environmental cues, including, the light-dark cycle and temperature. The SCN “gates” the activity of peripheral clocks in the liver, muscle, kidneys etc in a tissue-specific manner by relaying temporal information to the peripheral clocks via systemic signaling mechanisms such as the sympathetic nervous system as well as humoral factors (2).

Recently, there has been an increasing appreciation of the importance of the circadian clock in the temporal regulation of the cell cycle (3). Previous research has shown that the cell cycle is coupled to the circadian clock, with circadian rhythmicity in cell proliferation being observed in a number of organisms, including cyanobacteria, zebrafish, rodents and even humans, suggesting a strongly evolutionarily conserved link between the two systems (4). For instance, the DNA-replicative, S- and mitotic phases of the cell cycle tend to occur during the night, which is generally thought to enable the protection of these critical processes from harmful UV radiation during the day (5). In addition to the cell-autonomous influence of the circadian clock on the cell cycle, systemic signals such as growth factors, nutrients and hormones are also known to regulate the cell cycle. Often these systemic signals are also under the control of the circadian clock. One such critical mediator, cortisol, the primary stress response hormone, has both inhibitory and stimulatory influences on cell proliferation and the progression of the cell cycle (6). In addition, cortisol exhibits pronounced circadian rhythmicity and plays an important role in relaying temporal information from the central clock in the SCN to the peripheral circadian clocks.

It has been proposed that dysregulated entrainment of the cell cycle by the circadian clock might be involved in the development of cancer (7). Furthermore, evidence suggests that cell cycle desyncrhony in a population of proliferating cells leads to an impaired would healing response. Along these lines, glucocorticoid administration has been shown to synchronize the cell cycle resulting in more controlled proliferation in ex vivo disease models of asthma (8). In the present work, we develop a mathematical model, to study the influence of both the circadian clock as well as endogenous cortisol rhythms on the regulation of the cell cycle. Systems biology approaches are particularly suited to study such problems, given the complexity of feedback between the three dynamical systems. Our current model accounts for the dual influences of these two systems on the cell cycle by coupling a semi-mechanistic model for light entrainment on peripheral clock genes through the HPA axis previously developed by our group (9), to a skeletal model of the cyclin network developed by Gerard and Goldbeter (10). Furthermore, we model a population of cells in order to study the influence of cortisol and the circadian clock on the synchronization of the cell cycle. Current model results correctly predict a circadian dependence of the cell cycle, with most cells entering the DNA-replicative S phase towards the end of the light phase and the beginning of the dark phase. Moreover, we find a time-of-day dependent variation in the extent of cell cycle synchronization, with cells being most synchronized in the G1 phase in the early parts of the light phase. Importantly, the model predicts that the extent of synchronization in the population is dependent on the circadian dynamics of cortisol, with increasing cell cycle synchrony during the rising phase of cortisol in comparison to the falling phase. These results emphasize the ability of cortisol and the circadian clock to regulate cell cycle synchronization in a time-of-day dependent manner and provide a framework to assess how deviations from homeostatic cortisol rhythms might perturb the cell cycle.

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8. Freishtat RJ, Watson AM, Benton AS, Iqbal SF, Pillai DK, Rose MC, et al. Asthmatic airway epithelium is intrinsically inflammatory and mitotically dyssynchronous. Am J Respir Cell Mol Biol. 2011;44(6):863-9. doi: 10.1165/rcmb.2010-0029OC. PubMed PMID: 20705942; PubMed Central PMCID: PMCPMC3135846.

9. Mavroudis PD, Corbett SA, Calvano SE, Androulakis IP. Mathematical modeling of light-mediated HPA axis activity and downstream implications on the entrainment of peripheral clock genes. Physiological Genomics. 2014;46(20):766-78. doi: 10.1152/physiolgenomics.00026.2014.

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