Inhibition of casein kinase I ε/δ produces phase shifts in the circadian rhythms of Cynomolgus monkeys

Sprouse, Jeffrey; Reynolds, Linda; Swanson, Terri A.; Engwall, Michael

doi:10.1007/s00213-009-1503-x

Cited by 26 publications

(21 citation statements)

References 36 publications

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“…Our data now show that selective pharmacological suppression of the activity of CK1δ dose-dependently lengthens the period of circadian behavioral rhythms in vivo. This extends reports of the acute effects of single injections on activity onset in mice and primates (25,26). The apparent extension of the period we observed during repeated daily injection to WT mice in DD may arise either from a tonic increase in the period or represent the additive effects of a series of acute daily phase delays.…”

Section: Discussionsupporting

confidence: 85%

“…This issue is difficult to resolve, but the extension of the SCN period following continuous CK1δ inhibition in vitro argues for the former, parametric effect. However, the phase response curve to single PF-670462 injections in rats consists only of phase delays, and, although these are of largest amplitude for injection at CT12 and CT15, injections at all phases can delay the behavioral rhythm (25,26). Therefore, the apparent period lengthening that we observe in the mice could arise from serial nonparametric phase shifts.…”

Section: Discussionmentioning

confidence: 72%

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Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes

Meng

Maywood

Bechtold

et al. 2010

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

222

220

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Circadian pacemaking requires the orderly synthesis, posttranslational modification, and degradation of clock proteins. In mammals, mutations in casein kinase 1 (CK1) ε or δ can alter the circadian period, but the particular functions of the WT isoforms within the pacemaker remain unclear. We selectively targeted WT CK1ε and CK1δ using pharmacological inhibitors (PF-4800567 and PF-670462, respectively) alongside genetic knockout and knockdown to reveal that CK1 activity is essential to molecular pacemaking. Moreover, CK1δ is the principal regulator of the clock period: pharmacological inhibition of CK1δ, but not CK1ε, significantly lengthened circadian rhythms in locomotor activity in vivo and molecular oscillations in the suprachiasmatic nucleus (SCN) and peripheral tissue slices in vitro. Period lengthening mediated by CK1δ inhibition was accompanied by nuclear retention of PER2 protein both in vitro and in vivo. Furthermore, phase mapping of the molecular clockwork in vitro showed that PF-670462 treatment lengthened the period in a phase-specific manner, selectively extending the duration of PER2-mediated transcriptional feedback. These findings suggested that CK1δ inhibition might be effective in increasing the amplitude and synchronization of disrupted circadian oscillators. This was tested using arrhythmic SCN slices derived from Vipr2 −/− mice, in which PF-670462 treatment transiently restored robust circadian rhythms of PER2::Luc bioluminescence. Moreover, in mice rendered behaviorally arrhythmic by the Vipr2 −/− mutation or by constant light, daily treatment with PF-670462 elicited robust 24-h activity cycles that persisted throughout treatment. Accordingly, selective pharmacological targeting of the endogenous circadian regulator CK1δ offers an avenue for therapeutic modulation of perturbed circadian behavior.circadian clock | suprachiasmatic nucleus | period protein | Tau mutation | pacemaking

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 72%

Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes

Meng

Maywood

Bechtold

et al. 2010

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

222

220

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“…In tissue explants from PER2:LUC transgenic animals, increasing period length was observed with increasing concentrations of PF-670462, in this case using bioluminescence surrogates of clock gene rhythms (Walton et al 2009). As a consequence, the changes in behavioral rhythms noted previously in rodents (Badura et al 2007;Walton et al 2009) and monkeys (Sprouse et al 2009) appear grounded in changes at the level of cellular processes.…”

Section: Discussionmentioning

confidence: 91%

“…In particular, there is ample evidence to suggest that phosphorylation of per2 by casein kinase I ε/δ (CKI ε/δ) enhances its degradation (Eide et al 2002(Eide et al , 2005Xu et al 2005). Previous studies by our group with a selective small molecule inhibitor, PF-670462, revealed its ability to produce phase delays of the circadian activity rhythm in nocturnal (rat) and diurnal species (monkey) under conditions of light entrainment (Badura et al 2007;Sprouse et al 2009). The present study continues this line of research by establishing the impact of chronic once-daily dosing of PF-670462 on the phase relationship of the central pacemaker to the day/night cycle.…”

Section: Introductionmentioning

confidence: 97%

Chronic treatment with a selective inhibitor of casein kinase I δ/ε yields cumulative phase delays in circadian rhythms

et al. 2010

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The magnitude of the shifts in activity onsets achieved with chronic dosing of PF-670462 appears to be a function of the dose and the previously established phase relationship. Its cumulative effect further suggests that the pharmacodynamic t (1/2) of the drug greatly exceeds its pharmacokinetic one. Most importantly, these changes in circadian behavior occurred in the presence of a fixed L:D cycle, confirming the drug to be a robust modulator of circadian phase in the presence of the natural zeitgeber.

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“…Moreover, casein kinase-1δ is the principal regulator of the clock periods compared to casein kinase-1ε, because selective inhibition of casein kinase-1ε minimally alters circadian clock period [28,29]. Inhibition of casein kinase I epsilon/delta produces phase shifts in the circadian rhythms [30].…”

Section: Introductionmentioning

confidence: 99%

Expression of casein kinase genes in glioma cell line U87: Effect of hypoxia and glucose or glutamine deprivation

Minchenko¹,

Karbovskyi²,

Danilovskyi³

et al. 2012

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The endoplasmic reticulum-nuclei-1 (ERN1) sensing and signaling enzyme mediates a set of complex intracellular signaling events known as the unfolded protein response. We have studied the effect of hypoxia and ischemic conditions (glucose or glutamine deprivation) on the expression of several casein kinase-1 and -2 genes in glioma U87 cells and its subline with suppressed function of ERN1. It was shown that blockade of ERN1, the key endoplasmic reticulum stress sensor, leads to an increase in the expression levels of casein kinase-1G2, -1E, -2B and NUCKS1 mRNA, but suppresses casein kinase-1A1, -1D and -2A1. Moreover, the expression levels of casein kinase-1A1, -1D and 1G3 as well as casein kinase-2A1 and -2A2 mRNAs are significantly increased under glutamine deprivation conditions both in control and ERN1-deficient glioma cells. At the same time, casein kinase-1E, -2B and NUCKS1 mRNA expression levels are also increased under this condition, but only in cells with suppressed function of ERN1. The expression level of NUCKS1 mRNA, however, is decreased both in control glioma cells and in genetically modified cells, but casein kinase-1G2-only in control U87 cells. Cell exposure to glucose deprivation conditions enhances the expression levels of casein kinase-1D, 1G3, -1E and -2A1 in both types of glioma cells used, but casein kinase-2B expression levels increase only in cells with suppressed function of ERN1. Hypoxia induces or suppresses the expression of most of the studied genes mainly in ERN1-knockdown cells only. Results of this study show that hypoxia as well as glutamine and glucose deprivation conditions change the expression level most of casein kinase genes and that these effects are dependent on ERN1 signaling enzyme function.

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Inhibition of casein kinase I ε/δ produces phase shifts in the circadian rhythms of Cynomolgus monkeys

Cited by 26 publications

References 36 publications

Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes

Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes

Chronic treatment with a selective inhibitor of casein kinase I δ/ε yields cumulative phase delays in circadian rhythms

Expression of casein kinase genes in glioma cell line U87: Effect of hypoxia and glucose or glutamine deprivation

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