Figure 1.

Schematic of the molecular clock. Expression of the core clock proteins, BMAL1 and CLOCK, stimulates the production of PERIOD (PER1-3) and CRYPTOCHROME (CRY1-2) which, in turn, feedback-inhibit BMAL1 and CLOCK. The period of transcriptional-translational autoregulatory feedback loop is determined by the rate of degradation of PER and CRY by casein kinase 1 (CK1) δ/ε and F-box and leucine-rich repeat protein 3 (FBXL3), respectively. This generates an anti-phasic rhythm in the positive and negative arms of the clock, as illustrated for BMAL1 and PER2 during the day (yellow) and night (gray) periods. Additional input into the core clock is provided by retinoic acid receptor-related orphan receptor (ROR) α/β/γ, nuclear receptor subfamily 1 group D (REV-ERB) α/β, albumin D-box binding protein (DBP) and nuclear factor, interleukin 3 regulated (NFIL3).