![]() ![]() Most clock component messenger RNAs and protein has a 24-h oscillating rhythm except for fCLOCK, CKI delta and CKI epsilon (see review 23). ROR activates Bmal transcription, while REV-ERB inhibits it, which generate a rhythmic level of BMAL1 16, 22. ROR and REV-ERB translocate to the nucleus independently and bind to the Bmal promoter. In the nuclear, CRY suppresses CLOCK-BMAL1 induced transcription of Per, Cry, Ror and Rev-Erb in a negative feedback loop (see review 20). After PER reaches a critical level, it permits dimerisation with CRY and nuclear translocation. In the cytoplasm, PER is phosphorylated by several isoforms of casein kinase I (CKI), including CKI delta and CKI epsilon, which regulates the stability of PER and subcellular localization 17- 19. After transcription and translation, these proteins accumulate in the cytoplasm. The CLOCK-BMAL1 heterodimer is a transcriptional activator which binds to the E-box located upstream of the Period (Per), Cryptochrome (Cry), Retinoid-related Orphan Receptor (Ror) and Rev Erb genes 15, 16. A molecular machinery (transcription-translation feedback loops) drives circadian rhythms in both SCN and peripheral cells at transcription, translation, and posttranslational levels 13, 14. Evidence from animal and human studies demonstrates a genetic basis for the generation of circadian rhythms. In humans, the endogenous period of the circadian oscillation is slightly longer than 24 hours 12. Either disruption of the endogenous circadian control mechanism or misalignment between internal circadian rhythms with the 24-hour outside environment would result in circadian rhythm disorders with adverse consequences in sleep and many other aspects of human health, including metabolism dysfunction, cognitive impairment, cardiovascular abnormalities, gastrointestinal and genitourinary dysfunctions 10, 11. As a result, in virtually every physiological and behavioral parameter follows the roughly 24-hour (circadian) rhythms, among them the sleep/wake cycle is the most apparent. The SCN plays a pivotal role in coordinating circadian rhythmicity by communicating timing information to oscillators in tissues elsewhere in the brain, and almost all the peripheral tissues and organs 6- 9. It is composed of a network of ∼20,000 neurons in human and displays a self-sustained circadian (near 24 hour) rhythm in neuronal firing 2- 5. The suprachiasmatic nucleus (SCN), a paired structure in the anterior hypothalamus 1 is the site of a master circadian clock. Circadian rhythms are endogenous and persist in the absence of environmental time cues. Circadian rhythms are ubiquitous in all living organisms and nearly all physiological functions, most notably sleep and wake cycles, exhibit circadian rhythmicity. ![]()
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