Circadian-independent cell mitosis in immortalized fibroblasts

Abstract

Two prominent timekeeping systems, the cell cycle, which controls cell division, and the circadian system, which controls 24-h rhythms of physiology and behavior, are found in nearly all living organisms. A distinct feature of circadian rhythms is that they are temperaturecompensated such that the period of the rhythm remains constant (∼24 h) at different ambient temperatures. Even though the speed of cell division, or growth rate, is highly temperature-dependent, the cell-mitosis rhythm is temperature-compensated. Twenty-fourhour fluctuations in cell division have also been observed in numerous species, suggesting that the circadian system is regulating the timing of cell division. We tested whether the cell-cycle rhythm was coupled to the circadian system in immortalized rat-1 fibroblasts by monitoring cell-cycle gene promoter-driven luciferase activity. We found that there was no consistent phase relationship between the circadian and cell cycles, and that the cell-cycle rhythm was not temperature-compensated in rat-1 fibroblasts. These data suggest that the circadian system does not regulate the cell-mitosis rhythm in rat-1 fibroblasts. These findings are inconsistent with numerous studies that suggest that cell mitosis is regulated by the circadian system in mammalian tissues in vivo. To account for this discrepancy, we propose two possibilities: (i) There is no direct coupling between the circadian rhythm and cell cycle but the timing of cell mitosis is synchronized with the rhythmic host environment, or (ii) coupling between the circadian rhythm and cell cycle exists in normal cells but it is disconnected in immortalized cells.O rganization of physiology and behavior into specific time domains is a fundamental property of nearly all living organisms. Anticipation of periodic changes in the environment presumably increased survival and reinforced the development of endogenous circadian oscillators (1). Because cell division is critical to the survival of unicellular organisms and the integrity of DNA is susceptible to UV irradiation, the progression of the cell cycle was probably also strongly affected by daily changes in the environment. Indeed, multiple studies have measured diurnal fluctuations in cell division such that mitosis occurs at a specific time of day in numerous species ranging from unicellular organisms (2) to humans (3-5). These data suggest that the circadian and cell cycles may be coupled in vivo.Circadian rhythms are self-sustained oscillations in physiology and behavior with endogenous periods of ≈24 h that can be synchronized, or entrained, to environmental cues such as the light/dark cycle or temperature (6). In mammals, the master circadian clock is located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. Genes that are important for circadian timekeeping are expressed not only in the SCN but also in many peripheral tissues, including fibroblasts (7-11). Immortalized embryonic fibroblasts exhibit circadian rhythms of gene expression (12) and, using singlecell imaging...

Circadian clock-mediated control of stem cell division and differentiation: beyond night and day

“…For example, elimination of the SCN 'master clock' results in tumor growth two to three times faster than in controls (Filipski et al, 2002). Consistent with the possible importance of this regulation, clock protein misexpression and/or a lack of circadian control has been documented in multiple tumor types (Hwang-Verslues et al, 2013; Luo et al, 2012;Zhao et al, 2013) and immortalized cell lines (Yeom et al, 2010). In normal physiology, circadian cell division has been documented in adult hippocampal neurogenesis (BouchardCannon et al, 2013), in intestinal and skin epithelial cell division (Geyfman et al, 2012;Janich et al, 2013;Karpowicz et al, 2013), and in multiple immune cell populations (Fortier et al, 2011;Keller et al, 2009) -essentially anywhere that cell division occurs in adult animals.…”

Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle

“…Indeed, two recent studies reported a lack of clock regulation of the mammalian cell cycle (15,16). However, earlier work of Nagoshi et al (17) suggested a dynamical link distinct from 1:1 phase locking.…”

Local circadian clock gates cell cycle progression of transient amplifying cells during regenerative hair cycling

“…For such strategies to be viable, the circadian biology of cancer cells also has to be considered. Many types of cancer have an aberrant circadian clock (29), whereas mitotic progression in other types of cancer becomes asynchronous despite functional circadian oscillator (30,31). The concept of cancer chronotherapy that considers timing radio-and chemotherapy to maximize its cytotoxicity on tumor cells is continuing to gain experimental support (32).…”