Figure 1.

The circadian CLOCK system is regulated by a self-oscillating transcriptional loop.

The C heterodimer Clock/Bmal1 binds to E-box elements located in the promoter region and stimulates expression of essential clock transcription factors Pers and Crys (i), which in turn repress the transcriptional activity of the CLOCK/BMAL1 heterodimer by inhibiting its binding to the E-box response elements located in their own promoters through formation of a complex with and subsequent phosphorylation by the caseine kinase 1ε and δ (ii). Clock/Bmal1 also stimulates expression of other CLOCK-related proteins, such as Rev-erbα, RORα, Dec1, Dec2 and Dbp (iii), which create an auxiliary loop that helps stabilize the main regulatory loop. These clock transcription factors control numerous “downstream” CLOCK-responsive genes to influence a variety of biologic activities (iv). Bmal1: brain-muscle-arnt-like protein 1, Clock: circadian locomotor output cycle kaput, Crys: cryptochromes, Csnk1ε/δ: caseine kinase 1ε/δ, P: phosphate residue on the phsphorylated molecules, Pers: periods, RORγ: retinoic acid receptor-related orphan nuclear receptor γ.