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. Author manuscript; available in PMC: 2013 Jul 14.
Published in final edited form as: Annu Rev Neurosci. 2012 Apr 5;35:445–462. doi: 10.1146/annurev-neuro-060909-153128

Figure 1.

Figure 1

The molecular mechanism of the circadian clock in mammals. An autoregulatory transcriptional feedback loop involving the activators, CLOCK and BMAL1, and their target genes, Per1, Per2, Cry1 and Cry2, whose gene products form a negative feedback repressor complex, constitute the core circadian clock mechanism. In addition to this core transcriptional feedback loop, there are other feedback loops driven by CLOCK:BMAL1. One feedback loop involving Rev-erbα and Rorα that represses Bmal1 transcription leads to an antiphase oscillation in Bmal1 gene expression. CLOCK:BMAL1 also regulates many downstream target genes known as clock-controlled genes (Ccg). At a post-transcriptional level, the stability of the PER and CRY proteins is regulated by SCF (Skp1-Cullin-F-box protein) E3 ubiquitin ligase complexes involving β-TrCP and FBXL3, respectively. The kinases, casein kinase 1ε/δ (CK1ε/δ) and AMP kinase (AMPK) phosphorylate the PER and CRY proteins, respectively, to promote polyubiquitination by their respective E3 ubiquitin ligase complexes, which in turn tag the PER and CRY proteins for degradation by the 26S proteasome complex.