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. 2015 Apr 20;6:80. doi: 10.3389/fneur.2015.00080

Figure 2.

Figure 2

The two major TTLs of the circadian molecular clock in mammals (A) and Drosophila (B). (A) The first mammalian TTL includes BMAL1 and CLK, which act as heterodimer, binding the enhancer boxes (E-boxes) in the promoter of Per and Cry clock genes. PER and CRY proteins dimerize and enter into the nucleus, where inhibit the CLK -BMAL1 activity. A second loop modulates Bmal1 expression: CLK-BMAL1 dimers induce the transcription of Rev-erbα and Ror nuclear orphan receptor genes. REV-ERBs and RORs compete for the same element (Ror-E) in the Bmal1 promoter, controlling Bmal1 transcription. Phosphorylation mediated by CKs (δ/ε) and GSK3β modulate clock protein activities regulating protein–protein interactions, nuclear translocation, and degradation. Within the master clock, at the cell level, the light stimulus induces the transcription of the Per genes via a signal transduction cascade. (B) In the first TTL of Drosophila, CLK and CYC form a dimer, which binds the E-boxes in the promoter of per and tim clock genes. PER and TIM proteins interact in a complex, enter into the nucleus, and inhibit the CLK-CYC activity. A second TTL modulates Clk expression: CLK-CYC dimer induces the transcription of vri and Pdp1 δ/ε genes. VRI and PDP1 δ/ε compete for the same element (D-box) in the Clk promoter, controlling Clk transcription. Phosphorylation mediated by DBT and SGG modulate clock protein activities, regulating protein–protein interactions, nuclear translocation, and degradation. In the cell, light activates the internal photoreceptor CRY, which associates with TIM and mediates its degradation. BMAL: brain and muscle ARNT-Like 1; CKδ: casein kinase; CLOCK: circadian locomotor output cycles Kaput; CRY: cryptochrome; CYC: cycle; DBT: doubletime; GSK3β: glycogen synthase kinase 3 beta; PDP1: PAR domain protein 1; PER: period; REV-ERB: nuclear receptor subfamily 1, group D; ROR: RAR-related orphan receptor; TIM: timeless; VRI: vrille; SGG: Shaggy. Dashed arrows indicate phosphorylation, while sinusoidal lines indicate transcription activity.