Circadian Regulation of Kisspeptin in Female Reproductive Functioning - Kisspeptin Signaling in Reproductive Biology - page 376

Fig. 18.1 A simplifi ed model of the intracellular mechanisms responsible for mammalian
circadian rhythm generation. The process begins when CLOCK and BMAL1 proteins dimerize to
drive the transcription of the Per ( Per1 and Per2 ) and Cry ( Cry1 and Cry2 ) genes. In turn, Per and
Cry are translocated to the cytoplasm and translated into their respective proteins. Throughout the
day, PER and CRY proteins rise within the cell cytoplasm. When levels of PER and CRY reach a
threshold, they form heterodimers, feed back to the cell nucleus, and negatively regulate
CLOCK:BMAL1-mediated transcription of their own genes. This feedback loop takes approxi-
mately 24 h, thereby leading to an intracellular circadian rhythm. See text for additional details

by binding to the E-box (CACGTG) domain on their gene promoters. Once trans-
lated, PER and CRY proteins build in the cytoplasm of the cell over the course of
the day, and inevitably form hetero- and homodimers that feed back to the cell
nucleus to inhibit CLOCK:BMAL1-mediated transcription. The timing of nuclear
entry is balanced by regulatory kinases that phosphorylate the PER and CRY proteins,
leading to their degradation [ 21 , 24 , 25 ]. Two other promoter elements, DBP/E4BP4
binding elements (D boxes) and REV-ERB /ROR binding elements (RREs) [ 26 ],

also participate in cellular clock function. REV-ERB

α

, an orphan nuclear receptor,
negatively regulates the activity of the CLOCK:BMAL1. The same mechanism
controlling Per and Cry gene transcription also controls transcription of REV-
ERB

α

. Similarly, the transcription factor DPB is positively regulated by the
CLOCK:BMAL1 complex [ 27 ] and acts as an important output mechanism, driving
rhythmic transcription of other output genes via a PAR basic leucine zipper
(PAR bZIP) [ 28 ].

α