Fig. 1

Schematic view of the circadian pathway. CLOCK and NPAS2 form heterodimers with ARNTL (also known as BMAL1) or ARNTL2 (BMAL2); these heterodimers act as transcription factors binding to enhancer box (E-box) elements upstream of target genes. Besides the clock-controlled genes (CCGs), which mediate the circadian pathway physiological functions, CLOCK and NPAS2 activate the transcription of other core circadian genes such as PER1, PER2, PER3 and CRY1, CRY2. PER and CRY proteins heterodimerize and activate a negative feedback loop acting directly on CLOCK and NPAS2. The activity of PER and CRY proteins is also regulated by additional proteins such as CSNK1E and CSNK1D (inhibition) and TIMELESS (unclear effect), respectively. CLOCK and NPAS2 also transactivate the expression of other pathway components such as NR1D1, NR1D2 (also known as REV-ERBs) and RORA, RORB and RORC (which are transcription factors acting through ROR/REV-ERB elements): these proteins can inhibit or enhance ARNTL transcription, respectively, which adds a further level of modulation of CLOCK/NPAS2 activity. Green lines, stimulatory effect (positive loop); red lines, inhibitory effect (negative loop)