Casein Kinase I: Another Cog in the Circadian Clockworks

Eide, Erik J.; Virshup, David M.

doi:10.1081/cbi-100103963

Cited by 79 publications

(53 citation statements)

References 33 publications

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“…Rhythmic post-translational modifications of clock proteins, including phosphorylation of the PER-CRY complex by casein kinase 1 ε/δ (CKIε/δ) ( Fig. 1), introduces temporal delays that contribute to the 24 h period of the clock [37]. At the cellular level, the clock influences, and is influenced by, circadian rhythms in metabolism; daily variations in glucose uptake and metabolism influence the clock through metabolic sensors, such as adenosine monophosphate-activated protein kinase (AMPK) [38].…”

Section: The Internal Timing System and Metabolic Dysfunctionmentioning

confidence: 99%

Chronomedicine and type 2 diabetes: shining some light on melatonin

et al. 2016

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In mammals, the circadian timing system drives rhythms of physiology and behaviour, including the daily rhythms of feeding and activity. The timing system coordinates temporal variation in the biochemical landscape with changes in nutrient intake in order to optimise energy balance and maintain metabolic homeostasis. Circadian disruption (e.g. as a result of shift work or jet lag) can disturb this continuity and increase the risk of cardiometabolic disease. Obesity and metabolic disease can also disturb the timing and amplitude of the clock in multiple organ systems, further exacerbating disease progression. As our understanding of the synergy between the timing system and metabolism has grown, an interest has emerged in the development of novel clock-targeting pharmaceuticals or nutraceuticals for the treatment of metabolic dysfunction. Recently, the pineal hormone melatonin has received some attention as a potential chronotherapeutic drug for metabolic disease. Melatonin is well known for its sleep-promoting effects and putative activity as a chronobiotic drug, stimulating coordination of biochemical oscillations through targeting the internal timing system. Melatonin affects the insulin secretory activity of the pancreatic beta cell, hepatic glucose metabolism and insulin sensitivity. Individuals with type 2 diabetes mellitus have lower night-time serum melatonin levels and increased risk of comorbid sleep disturbances compared with healthy individuals. Further, reduced melatonin levels, and mutations and/or genetic polymorphisms of the melatonin receptors are associated with an increased risk of developing type 2 diabetes. Herein we review our understanding of molecular clock control of glucose homeostasis, detail the influence of circadian disruption on glucose metabolism in critical peripheral tissues, explore the contribution of melatonin signalling to the aetiology of type 2 diabetes, and discuss the pros and cons of melatonin chronopharmacotherapy in disease management.

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Section: The Internal Timing System and Metabolic Dysfunctionmentioning

confidence: 99%

Chronomedicine and type 2 diabetes: shining some light on melatonin

et al. 2016

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“…the target site, presumably because of interactions with the positively charged arginine at the CKI position 178 (10,13). However, these in vitro sites are nonconserved even between mammalian PER2s, strongly suggesting that they are irrelevant to cellular PER2 phosphorylation and function.…”

Section: Discussionmentioning

confidence: 99%

“…When tested in vitro on multiple substrates, CKI tau was shown to have a much reduced overall catalytic activity (10,12,13). This partial loss-of-function mutation and its phenotype have been difficult to reconcile with our current understanding of the molecular feedback loop that governs timing in mammalian cells (13) and recent empirical observations on clock function (14)(15)(16). For example, Dey et al (15) reported that PER proteins disappeared from the nucleus more rapidly in the tau hamster than in WT controls.…”

mentioning

confidence: 99%

“…CKI and the closely related CKI␦ are widely expressed serine-threonine protein kinases implicated in development, circadian rhythms, and DNA metabolism (11). When tested in vitro on multiple substrates, CKI tau was shown to have a much reduced overall catalytic activity (10,12,13). This partial loss-of-function mutation and its phenotype have been difficult to reconcile with our current understanding of the molecular feedback loop that governs timing in mammalian cells (13) and recent empirical observations on clock function (14-16).…”

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An opposite role for tau in circadian rhythms revealed by mathematical modeling

Gallego

Eide

Woolf

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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165

163

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Biological clocks with a period of Ϸ24 h (circadian) exist in most organisms and time a variety of functions, including sleep-wake cycles, hormone release, bioluminescence, and core body temperature fluctuations. Much of our understanding of the clock mechanism comes from the identification of specific mutations that affect circadian behavior. A widely studied mutation in casein kinase I (CKI), the CKI tau mutant, has been shown to cause a loss of kinase function in vitro, but it has been difficult to reconcile this loss of function with the current model of circadian clock function. Here we show that mathematical modeling predicts the opposite, that the kinase mutant CKI tau increases kinase activity, and we verify this prediction experimentally. CKI tau is a highly specific gain-of-function mutation that increases the in vivo phosphorylation and degradation of the circadian regulators PER1 and PER2. These findings experimentally validate a mathematical modeling approach to a complex biological function, clarify the role of CKI in the clock, and demonstrate that a specific mutation can be both a gain and a loss of function depending on the substrate.kinase ͉ systems biology ͉ phosphorylation ͉ PER ͉ degradation C ircadian rhythms govern key physiologic processes including sleep-wake cycles; glucose, lipid, and drug metabolism; heart rate; stress and growth hormones; and immunity, as well as basic cellular processes such as timing of the cell division cycle (1-6). The disruption of circadian rhythm causes significant physiologic stress, is frequently experienced in jet lag and night-shift work, and has been linked to bipolar disorder (7). Thus, circadian regulation of physiology has important consequences for health. A detailed quantitative model that makes clear, testable, and accurate predictions about the clock and how we may manipulate it can therefore have benefits for human health.Much of our understanding of clock components and their interactions began with the identification of mutations that affect circadian behavior (8, 9). In mammals, the original and most extensively studied circadian rhythm mutation is the semidominant tau, first described in 1988. Hamsters with this mutation show phase-advanced activity and have a circadian period of 20 h when homozygous mutant animals are isolated from time cues (9). This tau mutation has been identified as a missense mutation within the substrate recognition site of casein kinase I (denoted CKI tau ) (10). CKI and the closely related CKI␦ are widely expressed serine-threonine protein kinases implicated in development, circadian rhythms, and DNA metabolism (11). When tested in vitro on multiple substrates, CKI tau was shown to have a much reduced overall catalytic activity (10,12,13). This partial loss-of-function mutation and its phenotype have been difficult to reconcile with our current understanding of the molecular feedback loop that governs timing in mammalian cells (13) and recent empirical observations on clock function (14-16). For example, Dey et al. (1...

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“…1). Posttranslational mechanisms such as protein phosphorylation of negative (PER and CRY [22][23][24] ) and positive (CLOCK and BMAL1 25,26 ) components also play important roles in core clock activity.…”

Section: Circadian Clocks-a Universal Timing Mechanism Controlling Rementioning

confidence: 99%

Circadian Clock Genes as Modulators of Sensitivity to Genotoxic Stress

Antoch¹,

Kondratov²,

Takahashi³

2005

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=1792 KEY WORDSCircadian, CLOCK, BMAL1, transcription, anticancer therapy Review Circadian Clock Genes as Modulators of Sensitivity to Genotoxic Stress ABSTRACTA broad variety of organisms display circadian rhythms (i.e., oscillations with 24-hr periodicities) in many aspects of their behavior, physiology and metabolism. These rhythms are under genetic control and are generated endogenously at the cellular level. In mammals, the core molecular mechanism of the oscillator consists of two transcriptional activators, CLOCK and BMAL1, and their transcriptional targets, CRYPTOCHROMES (CRYS) and PERIODS (PERS). The CRY and PER proteins function as negative regulators of CLOCK/BMAL1 activity, thus forming the major circadian autoregulatory feedback loop. It is believed that the circadian clock system regulates daily variations in output physiology and metabolism through periodic activation/repression of the set of clock-controlled genes that are involved in various metabolic pathways. Importantly, circadian-controlled pathways include those that determine in vivo responses to genotoxic stress. By using circadian mutant mice deficient in different components of the molecular clock system, we have established genetic models that correlate with the two opposite extremes of circadian cycle as reflected by the activity of the CLOCK/BMAL1 transactivation complex.Comparison of the in vivo responses of these mutants to the chemotherapeutic drug, cyclophosphamide (CY), has established a direct correlation between drug toxicity and the functional status of the CLOCK/BMAL1 transcriptional complex. We have also demonstrated that CLOCK/BMAL1 modulates sensitivity to drug-induced toxicity by controlling B cell responses to active CY metabolites. These results suggest that the sensitivity of cells to genotoxic stress induced by anticancer therapy may be modulated by CLOCK/BMAL1 transcriptional activity. Further elucidation of the molecular mechanisms of circadian control as well as identification of specific pharmacological modulators of CLOCK/BMAL1 activity are likely to lead to the development of new anti-cancer treatment schedules with increased therapeutic index and reduced morbidity. ANTICANCER THERAPY-A DOUBLE-EDGED SWORDTwo major types of anticancer therapy-chemotherapy and radiation-were introduced into the clinic several decades ago and have demonstrated significant success in treating a variety of tumors. However, both types of anticancer therapy are compromised by accompanying nonspecific damage to normal tissues that often results in debilitating side effects. Well-known examples of such complications include the hematopoietic syndrome (induced by radiation and some DNA-damaging chemotherapeutic drugs, such as cyclophosphamide), direct neurotoxicity (induced by vinca alkaloids), damage to the oral mucosa, kidney and bladder, radiation-induced damage to intestinal epithelia, and many others. All of these si...

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Casein Kinase I: Another Cog in the Circadian Clockworks

Cited by 79 publications

References 33 publications

Chronomedicine and type 2 diabetes: shining some light on melatonin

Chronomedicine and type 2 diabetes: shining some light on melatonin

An opposite role for tau in circadian rhythms revealed by mathematical modeling

Circadian Clock Genes as Modulators of Sensitivity to Genotoxic Stress

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