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. Author manuscript; available in PMC: 2016 May 10.
Published in final edited form as: Trends Mol Med. 2014 Nov 5;20(12):685–693. doi: 10.1016/j.molmed.2014.10.007

Figure 1.

Figure 1

Feedback loop in the core circadian clocks. The clock machinery is composed of different feedback loops. In the primary loop, BMAL1 and CLOCK drive the transcriptional expression of PER and CRY through the activation of E-box enhancers. PER and CRY proteins form heterodimers that translocate to the nucleus, repressing their own transcription by interaction with CLOCK:BMAL1 complexes. The turnover of PER and CRY is also regulated by protein casein kinase 1 and AMP kinase, which phosphorylate these proteins, inducing their degradation in the cytosol by the 26S proteasome complex. This feedback in the primary loop occurs during 24 h and then, a new cycle starts. In another loop, CLOCK:BMAL1 heterodimers drive the expression of REV-ERB and ROR, which inhibit and activate BMAL1 expression, respectively. Some clock-controlled genes (CCGs), which are involved in metabolic pathways, are also under the modulation of the clock machinery. Abbreviations: BMAL1, brain and muscle ARNT-like 1; CLOCK, circadian locomotor output cycles protein kaput; PER, period homolog Drosophila; CRY, cryptochrome; REV-ERB, reverse-eritroblastosis virus; ROR, retinoic acid receptor-related orphan receptor; RORE, ROR response element.