Fig. 2.

Mammalian molecular circadian clock. Several core clock genes constitute interlocking molecular feedback loops. In this molecular clock, the bHLH-PAS (basic helix-loop-helix, Per-Arnt-Sim)-containing transcription factors BMAL1 and CLOCK function as positive regulators. Upon heterodimerization, they translocate into the nucleus, where they bind to the E-box enhancer element in the promoter region of downstream clock genes such as Periods (Pers) and Cryptochromes (Crys). Rhythmically expressed PER and CRY form a heterocomplex. In the nucleus, PER and CRY constitute a negative feedback loop by repressing their own transcriptional activation by CLOCK/BMAL1 heterodimer. The CLOCK/BMAL1 heterodimer also induces the transcription of the nuclear receptors Rev-erbα and Rorα. Rev-erbα and Rorα constitute another feedback loop by repressing and activating Bmal1 transcription, respectively.