FIGURE 2.

Central, peripheral, and molecular circadian clock. Light provides entrainment signals to the circadian clock, and the central and peripheral clocks coordinately regulate various organs of the human body and many biological processes, including hormone release, and blood pressure regulation. Molecular circadian clocks in mammals consist of the transcription factors “Clock” (circadian motor output cycle kaput) and “Bmal1” (brain and muscle aryl hydrocarbon receptor nuclear transporter 1), which bind to the E-box promoter to initiate transcription and subsequent so-called translation of clock-controlled genes (CCGs). Two clock-controlled genes are period (Per) and cryptochrome (Cry) family, and accumulation and dimerization of Per, Cry, CK1δ, and CK1ε lead to feedback inhibition that further inhibits Clock- and Bmal1-mediated transcription. Degradation of Per and Cry releases feedback inhibition and the cycle starts over. Second, Clock:Bmal1 heterodimer also activates the transcription of the Rve-erb family, which competes with Rev-erb/retinoic acid-related orphan receptor (ROR) binding elements. Third, Clock:Bmal1 heterodimer involves the PAR-bZip factors, including D-box binding protein (DBP), thyrotroph embryonic factor (TEF), and hepatic leukemia factor (HLF). These proteins interact at D-box-containing sites with the Rev-erb/ROR loop-driven repressor nuclear factor, interleukin 3 (NFIL3, also called E4BP4).