Fig. 2: The molecular mechanisms of mammalian circadian timekeeping through the autoregulatory transcriptional-translational feedback loops. | Translational Psychiatry

Fig. 2: The molecular mechanisms of mammalian circadian timekeeping through the autoregulatory transcriptional-translational feedback loops.

From: The trilateral interactions between mammalian target of rapamycin (mTOR) signaling, the circadian clock, and psychiatric disorders: an emerging model

Fig. 2

The transcription factors CLOCK (or NPAS2) and BMAL1 form heterodimers, which bind to the cis-acting element E-box and activate the expression of Period1/2 and Crypotochorme1/2. PER and CRY proteins form multiprotein complexes in the cytoplasm. Once accumulating to a certain level, the PER/CRY complexes translocate into the nucleus, interact with the CLOCK: BMAL1 complex, and repress their own gene transcription. The CLOCK: BMAL1 complex also promotes the transcription of Rev-erbα/β. REV-ERBs inhibit the Bmal1 transcription whereas RORs promote Bmal1 transcription. PER protein abundance is controlled at the mRNA translation level via an elF4E-dependent mechanism. CRY is phosphorylated by AMPK and PER by CSNK. The levels of CRY and PER are also regulated by phosphorylation and ubiquitin-medicated protein degradation at the post-translational levels. The CLOCK: BMAL1 complex also regulates numerous clock-controlled genes via the E-box enhancer.

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