Fig. 1

A general overview of molecular mechanisms. There are two vital genes for the generation of the circadian clock in the SCN cells, Clock gene and Bmal1 gene. The protein products of these genes form a heterodimeric CLOCK/BMAL1 complex in the cytoplasm. The CLOCK/BMAL1 complex translocates to the nucleus where it binds to specific E-box motifs and then drives the transcription of target genes including Cry1-2, Per1-3, and other downstream genes (PAR bZIP transcription factor genes TEF, DBP, HLE). The mRNAs of Pers and Crys are transcribed and then translated into PERs and CRYs in the cytoplasm. The increased PERs and CRYs dimerize and translocate into the nucleus where they reduce the transcriptional activity of the CLOCK/BMAL1 complex, resulting in restraint of their own transcription. Additional feedback loops begin when the transcription of two retinoic acid-related organ receptor response elements REV-ERBA and RORA is activated by the CLOCK/BMAL1 complex. The protein products of REV-ERBA (repressor of Baml1 transcription) and RORA (activator of Baml1 transcription) enter the nucleus where they competitively bind to the promoter of Baml1 gene to stimulate the expression of Baml1. The GATOR1 complex can suppress the activity of the mTOR pathway. The S6K1 kinase of the mTOR pathway can activate Baml1 via phosphorylation to regulate the function of BMAL1 and control circadian protein synthesis. mTORC1 regulates the phosphorylation-dependent S6K and eukaryotic translation initiation factor 4E-BPs. The activated S6K stimulates S6 phosphorylation while 4E-BP1 phosphorylation causes its dissociation from eIF4E, which increases protein synthesis and then leads to a rapid clock system regulation. Clock = circadian locomotor output cycles, Bmal1= brain and muscle ARNT-like 1, Cry = Cryptochrome, Per1 = Period, TEF = translation elongation factor, DBP = D-box binding protein, RORA = RAR-related orphan receptor α, REV-ERBA = reverse erythroblastosis virus α, mTOR = mammalian target of rapamycin, GATOR1 = GAP activity toward Rags 1, S6K1 = ribosomal S6 protein kinase 1, 4E-BP = 4E-binding protein, eIF4E = eukaryotic translation initiation factor 4e