Fig. 1.

Circadian feedback loops in mammalian cells. The loops contain the classical core feedback loop (including BMAL1/CLOCK and PER/CRY proteins), an REV-ERB/ROR loop, and a Dec loop, which interlocks with the classical core loop. CLOCK and BMAL1 form heterodimers that activate the transcription of Cry and Per genes. PER dimerizes with CRY to inhibit CLOCK–BMAL1-mediated transcription. Rora activates the expression of BMAL1, and Rev-erbα inhibits it, forming a feedback loop. The CLOCK and BMAL1 complexes activate transcription of the Dec1 and Dec2 genes, whereas the PER and CRY complexes inhibit them. In addition, DECs self-regulate to inhibit the transcription of their own genes. This forms another loop. These loops are interlocked. CK1ε/δ, casein kinase 1ε/δ; CRY, cryptochrome; DEC, differentiated embryo chondrocyte; E-box, enhancer-box; PER, period; ROR, retinoic acid-related orphan receptor; P, phosphorylation.