Figure 1.

A simplified model of the mammalian circadian clock mechanism. Bmal1 and Clock proteins bind at E-box enhancer elements present in the promoters of Rorα, Rev-Erbα, Cry and Per genes and drive their expression in the nucleus. Complexes of Per and Cry proteins in the nucleus inhibit Clock/Bmal1 action by an unknown mechanism, thereby down-regulating their own expression and that of Rorα and Rev-Erbα. Absence of Rev-Erbα protein derepresses Bmal1 and possibly also Clock, and their proteins reinitiate a new circadian cycle. How the timing between Rev-Erbα and RORα proteins is established is not understood. An essential feature of the clock is posttranslational modification. Casein kinase I (CKI) ε and δ isoforms phosphorylate Per, Cry and Bmal1 proteins, decreasing their stability and therefore critically regulating the time of action of clock proteins. Periodic gene expression is indicted by a single wave.