Figure 1

A simplified depiction of the mammalian molecular circadian clock machinery. Light perceived by the retina is the most potent synchronizer of the SCN clock. The circadian clock consists of positive and negative autoregulatory feedback loops. The oscillator is composed of interlocking transcription/translational feedback loops, controlling circadian timing. The CLOCK:BMAL1 or CLOCK:NPAS2 heterodimer (positive elements) is the “core loop” and induces E-box-mediated transcription of Per, Cry and Dec; their products are cyclically released in the cytoplasm. When PER and CRY proteins reach a critical concentration, they form heterodimers PER:CRY (negative elements), phosphorylate and translocate into the nucleus, where they inactivate the BMAL1:CLOCK or BMAL1:NPAS2 E-box-mediated transcription, including transcription of their own genes, which reduces their levels sufficiently to allow for the new transcription cycle. In addition, DECs bind to the E-box element of their promoter and inhibit their own transcription directly. CLOCK:BMAL1 also controls the levels of the nuclear receptors retinoid-related orphan receptor α (RORα) and Rev-erbα (known as nuclear receptor subfamily 1, group D, member 1 (NR1D1)), which constitute the “stabilizing/auxiliary loop” by repressing BMAL1 concentration via competitive actions on the retinoic acid-related orphan receptor response element (RORE) (black diamond shape) in the Bmal1promoter. Cycling of clock components by the core and stabilizing/auxiliary loops also promotes cyclic accumulations of clock-controlled gene (CCG) mRNA species, thus achieving an oscillating pattern and generating rhythmic physiological outputs in a cell type-specific fashion (steroid biosynthesis, cell cycle progression/arrest, cell proliferation, apoptotic pathways, immune function, hormonal oscillations, body temperature, metabolism, DNA repair, response to anticancer drugs and so on). E-boxes (white rectangle shape): regulatory enhancer sequences present in the promoter regions of the genes to which CLOCK:BMAL1 heterodimer binds. Casein kinase (CK) isoforms phosphorylate PER and CRY proteins modulating the nucleocytoplasmic translocation of core clock elements and thereby their transcriptional activity.