Closing the Circadian Loop: CLOCK-Induced Transcription of Its Own Inhibitors
            <i>per</i>
            and
            <i>tim</i>

Darlington, Thomas K.; Wager-Smith, Karen; Ceriani, M. Fernanda; Staknis, David; Gekakis, Nicholas; Steeves, Thomas; Weitz, Charles J.; Takahashi, Joseph S.; Kay, Steve A.

doi:10.1126/science.280.5369.1599

Cited by 776 publications

(776 citation statements)

References 26 publications

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“…In the heads of wild-type adults challenged with a 1808 phase shift in their environmental temperature cycle, per transcript reacted quickly with an increase in rhythmic amplitude and an apparent advance in phase, whereas about 20 h later both a phase advance in tim transcript and a phase delay in PER and TIM protein were initiated. tim and per mRNA and protein rhythms are known to be functionally linked in the circadian cycle in a number of ways: (i) of course, PER and TIM protein are produced from per and tim transcript; (ii) TIM protein is known to stabilize PER protein by preventing DOUBLETIME-mediated phosphorylation and subsequent turnover of PER protein [31]; and (iii) PER and TIM feedback negatively on the expression of per and tim transcripts via PER-mediated inhibition of the CLK/CYC transcription factor [32]. As per transcript is the first to show temperature-mediated resetting, its response cannot be a secondary consequence of a phase shift in tim transcript or PER or TIM protein.…”

Section: Discussionmentioning

confidence: 99%

Temperature-dependent resetting of the molecular circadian oscillator inDrosophila

2014

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Circadian clocks responsible for daily time keeping in a wide range of organisms synchronize to daily temperature cycles via pathways that remain poorly understood. To address this problem from the perspective of the molecular oscillator, we monitored temperature-dependent resetting of four of its core components in the fruitfly Drosophila melanogaster: the transcripts and proteins for the clock genes period ( per) and timeless (tim). The molecular circadian cycle in adult heads exhibited parallel responses to temperature-mediated resetting at the levels of per transcript, tim transcript and TIM protein. Early phase adjustment specific to per transcript rhythms was explained by clockindependent temperature-driven transcription of per. The cold-induced expression of Drosophila per contrasts with the previously reported heatinduced regulation of mammalian Period 2. An altered and more readily reentrainable temperature-synchronized circadian oscillator that featured temperature-driven per transcript rhythms and phase-shifted TIM and PER protein rhythms was found for flies of the 'Tim 4' genotype, which lacked daily tim transcript oscillations but maintained post-transcriptional temperature entrainment of tim expression. The accelerated molecular and behavioural temperature entrainment observed for Tim 4 flies indicates that clock-controlled tim expression constrains the rate of temperature cycle-mediated circadian resetting.

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Section: Discussionmentioning

confidence: 99%

Temperature-dependent resetting of the molecular circadian oscillator inDrosophila

2014

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“…Even if we believe nowadays that many of the phenotypes observed with these mice were due to a gain-of-function phenotype of the resulting mutant CLOCK D19 protein, its impact on the model building of the mammalian circadian oscillator was tremendous. After the identification of CLOCK's function as a transcriptional activator operating via so-called E-box motifs [9,10], a model based on a transcriptional and posttranslational feedback loop integrating positive and negative elements was proposed for mammals [11] (see Fig. 1).…”

Section: Disturbing Rhythms Of Micementioning

confidence: 99%

The daily rhythm of mice

2011

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Edited by Martha Merrow and Michael BrunnerKeywords: Clock mutant mice Metabolism Cancer Neurological disease Mood Obesity a b s t r a c tThe house mouse Mus musculus represents a valuable tool for the analysis and the understanding of the mammalian circadian oscillator. Forward and reverse genetics allowed the identification of clock components and the verification of their function within the circadian clockwork. In many cases unforeseen links were discovered between a particular circadian regulatory protein and various diseases or syndromes. Thus, this model system is not only perfectly suited to pinpoint the components of the mammalian circadian clock, but also to unravel metabolic, physiological, and pathological processes linked to the circadian timing system.

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“…CLOCK heterodimerizes with BMAL1 to drive the rhythmic expression of mPer and mCry. 7,8 After accumulating in the cytoplasm, PER and CRY proteins heterodimerize and translocate toward the nucleus, where they regulate the activity of CLOCK:BMAL1, completing a transcriptional/ translational feedback loop. 9,10 Therefore, the peak expression of these two distinct sets of genes occurs in the SCN in antiphase with respect to each other.…”

Section: Introductionmentioning

confidence: 99%

Clock genes are implicated in the human metabolic syndrome

et al. 2007

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Background: Clock genes play a role in adipose tissue (AT) in animal experimental models. However, it remains to be elucidated whether these genes are expressed in human AT. Objective: We investigated the expression of several clock genes, Bmal1, Per2 and Cry1, in human AT from visceral and subcutaneous abdominal depots. A second objective was to elucidate whether these clock genes expressions were related to the metabolic syndrome features. Methods: Visceral and subcutaneous AT samples were obtained from morbid obese men (n ¼ 8), age: 42713 years and body mass indexX40 kg/m 2 , undergoing laparoscopic surgery due to obesity. Biopsies were taken as paired samples at the beginning of the surgical process (1100 hour). Metabolic syndrome features such as waist circumference, plasma glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol and low-density lipoprotein (LDL) cholesterol were also studied. Homeostasis model assessment index of insulin resistance was also calculated. The expression of the different clock genes, hBmal1, hPer2 and hCry1, was determined by quantitative real-time PCR. Results: Clock genes were expressed in both human AT depots. hBmal1 expression was significantly lower than hPer2 and hCry1 in both AT (Po0.001). All genes were highly correlated to one another in the subcutaneous fat, while no correlation was found between Bmal1 and Per2 in the visceral AT. Clock genes AT expression was associated with the metabolic syndrome parameters: hPer2 expression level from visceral depot was inversely correlated to waist circumference (Po0.01), while the three clock genes studied were significantly and negatively correlated to total cholesterol and LDL cholesterol (Po0.01). Conclusion: We have demonstrated for the first time in humans that clock genes are expressed in both subcutaneous and visceral fat. Their association with abdominal fat content and cardiovascular risk factors may be an indicator of the potential role of these clock genes in the metabolic syndrome disturbances.

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Closing the Circadian Loop: CLOCK-Induced Transcription of Its Own Inhibitors per and tim

Cited by 776 publications

References 26 publications

Temperature-dependent resetting of the molecular circadian oscillator inDrosophila

Temperature-dependent resetting of the molecular circadian oscillator inDrosophila

The daily rhythm of mice

Clock genes are implicated in the human metabolic syndrome

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