Figure 1. Schematic representation of molecular interactions in mammalian circadian transcriptional negative feedback loops.

For simplicity, many cells and tissues have the capacity to oscillate with a wide variety of periodicities, and the circadian oscillators can be entrained to local time in response to environmental stimuli including daylight, temperature and feeding availability. Firstly, the interactions between positive elements (BMAL1 and CLOCK) and negative elements (CRY and PER) which form the interconnect negative feedback loop in mammals through inhibiting CLOCK-BMAL1-dependent transcription. Then, RORα and Rev-ERBα, which form the secondary loop that regulates rhythms, resulting from the activation and inhibition the expression of BMAL1, respectively. Finally, phosphorylation and ubiquitination of the negative components results in their eventual degradation, allowing the positive components to restart the cycle.