Figure 1.

The core mammalian molecular clock. The core biological clock is comprised of a positive arm in which BMAL1 and CLOCK heterodimerize to induce expression of the negative arm consisting of PER and CRY, which then feed back to inhibit Bmal1 and Clock. Additionally, BMAL1/CLOCK activate Rev-Erbα/β and RORα/γ, which have opposing roles in regulation of Bmal1, whereby Rev-Erbα/β stimulates and RORα/γ inhibits Bma1l expression. The rate of PER and CRY degradation, mediated by CK1δ/ε and F-box/leucine rich-repeat protein 3, generates the 24-hour circadian period. Finally, transcriptional regulation of clock-controlled genes (CCGs) by the core clock establishes a circadian rhythm in a wide range of cellular functions. BMAL, brain and muscle ARNT-like 1; CK1, casein kinase 1; CLOCK, circadian locomotor output cycles kaput; CRY, cryptochrome; PER, period.