Schematic representation of the mammalian circadian clock mechanism. ROREs are retinoic acid-related orphan nuclear receptor response elements present in Bmal1 promoter to which REV-ERBs and RORs compete to bind whereas E-boxes are regulatory enhancer sequences present in the promoter regions of the genes under consideration to which CLOCK-BMAL1 heterodimer binds. Casein kinase (CK) isoforms phosphorylate PER, CRY and BMAL1 proteins decreasing their stability and critically regulating the time of action of clock proteins. Similarly, targets of GSK3 (glycogen synthase kinase-3) include PER, REV-ERBα and CRY2. c-Myc, Wee1 and Cyclin D1 are clock-controlled cell cycle genes.