Circadian Clock, Cell Division, and Cancer: From Molecules to Organism

Abstract

As a response to environmental changes driven by the Earth's axial rotation, most organisms evolved an internal biological timer-the so called circadian clock-which regulates physiology and behavior in a rhythmic fashion. Emerging evidence suggests an intimate interplay between the circadian clock and another fundamental rhythmic process, the cell cycle. However, the precise mechanisms of this connection are not fully understood. Disruption of circadian rhythms has a profound impact on cell division and cancer development and, vice versa, malignant transformation causes disturbances of the circadian clock. Conventional knowledge attributes tumor suppressor properties to the circadian clock. However, this implication might be context-dependent, since, under certain conditions, the clock can also promote tumorigenesis. Therefore, a better understanding of the molecular links regulating the physiological balance between the two cycles will have potential significance for the treatment of cancer and associated disorders.

Keywords: cancer; circadian disruption; clock-controlled genes; proliferation; the cell cycle; the circadian clock.

Figure 1

The circadian transcriptional/translational feedback loop (TTFL) machinery in mammals. In the core loop CLOCK/BMAL1 bind E-boxes in promoters of target genes (Pers, Crys, and clock-controlled genes (CCGs)) and activate transcription. Nuclear export and translation of obtained mRNAs allows gradual accumulation of PERs and CRYs in the cytoplasm. Kinases, such as CKI and 5′ AMP-activated protein kinase (AMPK), adjust the period of the clock by phosphorylation and subsequent degradation of PER and CRY proteins, respectively. PERs and CRYs form complexes, which enter the nucleus and inhibit CLOCK/BMAL1-mediated transcription. Consequent degradation of PERs and CRYs restarts a new cycle of transcription. Accessory loops contain additional pairs of antagonizing transcription factors such as REV-ERBs (α/β) and RORs (α/β/γ), or DBP (D-box-binding protein) and E4BP4 (E4 promoter-binding protein 4). The former regulates Clock and Bmal1 genes through ROR-elements (RORE), whereas the latter controls the expression of other CCGs via D-boxes at a second hierarchical level.

Figure 2

Schematic view of coupling between the circadian clock and the cell cycle in healthy and tumor cells. The circadian oscillator based on TTFLs and the cell cycle, consisting of several phases regulated by CDK/cyclin complexes, coexist in a single cell. The clock is entrained by systemic signals from the body and by the internal energetic state of the cell, whereas cell cycle progression depends on a combination of other factors, such as mitogenic stimulation, tumorigenic mutations, and DNA damage checkpoints. Interaction of both oscillators, as defined by specific coupling factors, determines the circadian timing of cell division (for details see Section 3 and Section 4).