The periodic expression of clock genes is driven by Per and Cry inhibiting the activity of the CLOCK/BMAL1 dimer (negative feedback) and stimulating Bmal1 gene transcription (positive feedback). Through a negative feedback loop, the heterocomplex CLOCK/BMAL1 activates the transcription of period (Per) and cryptochrome (Cry) genes upon binding to the E-box promoter region. After the expression of PER/CRY proteins in the cytoplasm, they translocate to the nucleus where they inhibit their own transcription by shutting off the transcriptional activity of the CLOCK/BMAL1 heterocomplex . Through the positive feedback loop the nuclear compartment of PER/CRY protein (y3) activates indirectly Bmal1 mRNA (y4) transcription, which after its translation to BMAL1 protein and its translocation to the nucleus, increases the expression of CLOCK/BMAL1 heterodimer. However, the peripheral clocks are “entrained” by external signals – cortisol (F) in this case. The role of the entertainer is to synchronize the responses across a collection of cells. Figure adapted from .