ETDs: Doctoral Theses

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Browsing ETDs: Doctoral Theses by Author "Baxter, Beverly Joan"

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    Impairment in mitochondrial oxidative phosphorylation alters clock gene expression
    (2020-10-21) Baxter, Beverly Joan
    Epidemiological studies provide evidence that workers who perform chronic night shift work are at significantly higher risk of a number of severe disease states including cancer. The perturbed activity/rest and feeding/fasting cycles, which occurs in persons performing shift work or who are subjected to jet lag, disrupt our normal 24- hour internal clock or circadian rhythm. The molecular mechanisms that link chronic circadian disruption to disease are not well understood. Since light exposure at night is known to decrease melatonin levels, some researchers have hypothesized that a reduction in the nocturnal levels of this pineal hormone predisposes individuals to disease. Animals that displayed atypical behaviours in their daily cycles, led to the identification of eight-key clock or circadian genes that are differentially expressed during the day and which determine normal internal timing. The expression of these genes was abnormal in a large number of human tumors including breast cancer. In this study, a temperature shift model was characterized and used as a means to synchronize the expression of these clock genes in a human breast cancer cell line. The model was compared to another cell synchronization protocol which utilizes serum shock and which showed differences in gene expression and cell cycle regulation between the two protocols. The temperature shift model was then used to study the impact of melatonin on clock gene expression and on the production of reactive oxygen species (ROS) in cells exposed to chemotherapeutic drugs. Melatonin influenced the cell cycle but did not cause significant differences in clock gene expression. Chemotherapeutic drugs differed in their effects on the production of intracellular ROS. A mitochondrial deficient (Rhø) cell line which exhibited impaired oxidative phosphorylation, was developed from MCF-7 cells. The profile of clock gene expression in Rhø cells that were also subjected to the temperature shift protocol was different than that of the parental MCF-7 line. This suggests that impairment of mitochondrial function disrupts clock gene expression and may be a link to the oncogenic transformation of cells.