1. Life's 24-hour clock: molecular control of circadian rhythms in animal cells 
Michael W Young 
Trends in Biochemical Sciences 
Volume 25, Issue 12, Pages (December 2000)
DOI: /S (00)

2. Fig. 4
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3. Fig. 1
The Drosophila clock. The per and tim genes are coordinately activated by dCLK (C) and CYC (B)4,6. The per and tim RNAs (∼) are translated to form PER (P) and TIM (T) proteins that must heterodimerize to enter the nucleus3,4. Nuclear PER–TIM complexes and nuclear PER cause weak and strong suppression of dCLK–CYC activity, respectively3,4,8, and thus autoregulate per and tim transcription; PER and TIM also promote dClk gene expression28,29. Cytoplasmic heterodimerization of PER and TIM is retarded by the kinase DBT (D), which promotes the phosphorylation (orange circle) and degradation of PER proteins15,16. Unlike PER, PER–TIM complexes are stable in the presence of DBT. Kinase-dependent delays in PER accumulation are required for cycling expression of per and tim15. DBT also regulates PER phosphorylation and degradation in the nucleus. TIM proteins are degraded in the presence of light, which entrains molecular oscillations to the phase and period of environmental light–dark cycles3,4,6. The effects of light on TIM are mediated by the flavoprotein CRY in a cell-autonomous fashion6. Dashed arrows show delays.
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4. Fig. 2
The mammalian clock. Depending on the cell type18, up to three per genes and two cry genes are activated by CLK (C) and BMAL1 (B). Heterodimerization of PER (P) proteins or the interaction of the PER and CRY proteins facilitates PER nuclear localization18,27. PER and CRY proteins suppress CLK–BMAL1 activity4,18,23,27 and at least one PER protein (PER2) modestly promotes bmal1 gene expression20. Although CLK–BMAL1 suppression by a PER–CRY heterodimer is shown here, it is not clear how many classes of PER- and/or CRY-containing complexes are active in vivo18,20,23,27. The possibly overlapping roles of CRY and PER proteins also complicate genetic analysis of the individual contributions of PER1, PER2, PER3, CRY1 and CRY2 (Refs 11,19,20). Nuclear localization of PER is retarded in cultured cells by casein kinase Ie (TAU) dependent phosphorylation (orange circle), which affects the PER nuclear localization signal32 (NLS). This kinase is an ortholog of Drosophila DBT and is affected by the hamster circadian mutant tau 31. PER's phosphorylation by casein kinase Ie also appears to foster PER degradation33.
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5. Fig. 3
Rhythmic expression of factors mediating circadian behavior are controlled by oscillating activities of dCLK and CYC. The neuropeptide PDF influences the expression of locomotor activity rhythms in Drosophila 41. PDF accumulates with a circadian rhythm in nerve processes formed by pacemaker cells of the fly brain40. Constant production of PDF interferes with rhythmic behavior 43 but pulses of PDF can reset the phase of the behavioral rhythm42, suggesting roles for PDF in both behavioral output and entrainment of the molecular clockworks (black arrows). Cycling vri expression is required for PDF accumulation and for the molecular oscillations of per and tim, indicating a role for VRI in the oscillator itself (red line) and in the oscillator's output and entrainment through effects on PDF44 (black line). Cycling vri transcription is generated by dCLK–CYC binding of the vri promoter and periodic suppression by PER and TIM44. In mammals, oscillating expression of vasopressin and Dbp, a distant relative of vri, are similarly regulated by inter-actions of CLK–BMAL1 with the vasopressin and Dbp promoters45,49,50.
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