Abstract
Physiology is an integrative science. The study on circadian clocks, those having period of approximately 24 hours, is a representative field of this integrative analysis from genes to behavior or physiology. Circadian rhythms are generated in pacemaker cells, the hypothalamic suprachiasmatic nuclei (SCN) in mammals, and entrained by environmental cues such as light and temperature. The output of a circadian oscillation appears as locomotive activity, hormonal secretion, the sleep-wake cycle, and other physiological processes. Recent molecular dissection for last several years has revealed that circadian rhythms are based on transcriptional regulation of clock and clock-controlled genes, and the interlocked feedback- and feedforward-loop of transcription is the basic concept of the circadian oscillator, conserved across the species. For the well-known example, the transcription of Per1 is activated by the binding of the CLOCK/BMAL1 hetero-complex, both of which are bHLH-PAS proteins, to the E-boxes in the promoter region of Per1. The translated PER1, together with other clock proteins, is returned into the nucleus to suppress its own transactivation, resulting in closing of a PER1 loop. On the other hand, BMAL1, which is a positive element to PER1, has itself another loop. New transcriptional regulation and oscillation by other molecules including orphan nuclear receptors, Rev-erb and ROR, in the BMAL1 loop will be described and discussed. [Jpn J Physiol 54 Suppl:S39 (2004)]
