Cox, C.A.; (2012) The circadian clock and the cell cycle. Doctoral thesis , UCL (University College London).

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Abstract

The circadian clock is an endogenous time-keeping mechanism that allows an organism to coordinate its biology with the 24 hour variations in its external environment. Epidemiological studies have linked clock disruption to an increase incidence of cancer, in particular breast malignancy. On a molecular level, clock components have been shown to regulate cell cycle gene expression and its progression in a number of models. This thesis set out to further dissect the link between these two important systems. Within the zebrafish cell-line, PAC2, mitosis was demonstrated to be under circadian control via clock regulation of the cell cycle mediator, Cyclin B1. Techniques used were then translated into a human cell-line model to study species specific clock function, with particular reference to breast epithelial tissue. Glucocorticoids, putative clock synchronisation agents in vivo, were observed to induce cellular clock synchronisation in HEK 293 cells and the benign breast epithelial cell-line MCF10A. Clock disruption inhibited cell growth. Study of the breast epithelial cell cycle mutant, MDA-MB-231, demonstrated a functional clock, revealing no reciprocal regulation. In contrast, decreased expression levels of clock gene and putative tumour suppressor, Per1, were observed within the malignant breast epithelial cell-line, MCF7, leading to greatly disrupted clock function and circadian independent cell growth. Unlike the zebrafish model, no intracellular clock regulation of cell cycle genes expression or function was observed, expression being preferentially modified by homeral circadian regulators such as glucocorticoids and melatonin. This also contradicts mammalian in vivo studies, leading to the hypothesis that the clock and cell cycle maybe uncoupled in immortalised cell cultures. In conclusion this study has demonstrated that clock regulation of the cell cycle in mammalian system is a multifactorial process and that disruption of this system leads to changes in the character of the cell cycle within the host tissue. Further work must explore this relationship in an in vivo setting.

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