Human casein kinase Iδ phosphorylation of human circadian clock proteins period 1 and 2

Camacho, Fernando; Cilio, Maria Roberta; Guo, Yixuan; Virshup, David M.; Patel, Kamala D.; Khorkova, Olga; Styren, Scot; Morse, B; Yao, Zhengbin; Keesler, George A.

doi:10.1016/s0014-5793(00)02434-0

Cited by 138 publications

(101 citation statements)

References 26 publications

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“…This enhanced nuclear localization may be due to a net increase in overall cellular PER concentrations, as a consequence of the reduced degradation of the PER target by CK1 inhibition (20). CK1-mediated phosphorylation of PER is known to affect nuclear translocation of the protein (9)(10)(11) and therefore may also contribute to the nuclear retention we observed.…”

Section: Discussionmentioning

confidence: 71%

“…In Drosophila, mutations of doubletime (dbt, an ortholog of mammalian CK1) result in either short (dbt s ) or long (dbt l ) circadian rhythms (6,7). In mammals, both CK1ε and CK1δ can complex with PER and CRY (8) and phosphorylate PER proteins, leading to proteasome-mediated degradation and nuclear translocation (9)(10)(11). In humans, familial advanced sleep phase syndrome (FASPS) is associated with a T44A missense mutation in CK1δ, leading to hypophosphorylation of PER2 in vitro (12), although in Syrian hamsters and mice, the CK1ε tau mutation results in hyperphosphorylation and subsequent destabilization of its PER targets with significant shortening of behavioral activity cycles to 20 h (13-16).…”

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confidence: 99%

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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.

224

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: Discussionmentioning

confidence: 71%

mentioning

confidence: 99%

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.

224

220

View full text Add to dashboard Cite

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“…Indeed, it has been demonstrated that CKIε and CKIδ are involved in the phosphorylation of the mammalian PER proteins (Keesler et al 2000;Camacho et al 2001;Akashi et al 2002;Schlosser et al 2005). Moreover, CKIε is able to phosphorylate BMAL1 and CRY proteins in vitro (Eide et al 2002).…”

Section: Kinases and Phosphatasesmentioning

confidence: 99%

“…In a very similar manner, mammalian PER proteins are extensively phosphorylated by CKIε and CKIδ, thereby reducing the stability of the proteins by targeting them for proteasomal degradation (Keesler et al 2000;Camacho et al 2001;Akashi et al 2002). PER proteins are recognized by the Slimb homologs β-TrCP1/2 as parts of the SCF ubiquitin ligase complex.…”

Section: Phosphorylation Regulates Subcellular Localizationmentioning

confidence: 99%

Role of Phosphorylation in the Mammalian Circadian Clock

Vanselow¹,

Kramer²

2007

Cold Spring Harbor Symposia on Quantitative Biology

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Circadian clocks regulate a wide variety of processes ranging from gene expression to behavior. At the molecular level, circadian rhythms are thought to be produced by a set of clock genes and proteins interconnected to form transcriptional-translational feedback loops. Rhythmic gene expression was formerly regarded as the major drive for rhythms in clock protein abundance, but recent findings underline the crucial importance of posttranslational mechanisms for both the generation and dynamics of circadian rhythms. In particular, the reversible phosphorylation of PER proteins-essential components within the negative feedback loop in Drosophila and mammals-seems to have a key role for the correct timing of nuclear repression. To understand how PER protein phosphorylation regulates the dynamics of the circadian oscillator, we have mapped endogenous phosphorylation sites in mPER2. Detailed investigation of the functional role of one particular phosphorylation site (Ser-659, which is mutated in the familial advanced sleep phase syndrome [FASPS]) led us propose a model of functionally different phosphorylation sites in PER2. This concept explains not only the FASPS phenotype, but also the effect of the tau mutation in hamster.

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“…52 In addition, the PAR-leucine zipper transcription factor albumin D element-binding protein (DBP) is a first-order clock-controlled gene directly regulated by BMAL1/ CLOCK; 53 it also plays a role in the core clock by activating Per1 transcription. 54 Kinases such as CKId, 55,56 CKIe 57,58 and GSK3b 25,59 play an important role in phosphorylation of clock proteins, thus regulating the activity, nuclear entry and degradation of various core clock components. Among these kinases, GSK3b is of particular interest here because it was reported to be one of the direct targets of lithium, 60 which is an effective therapy for bipolar disorder.…”

Section: Introductionmentioning

confidence: 99%

Assessment of circadian function in fibroblasts of patients with bipolar disorder

et al. 2008

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Previous studies have implicated the circadian system in the pathophysiology of bipolar disorder, but conclusive evidence for altered circadian clocks is lacking. Cultured fibroblasts harbor circadian clocks representative of those in the master clock resident in the suprachiasmatic nuclei, providing a new avenue to investigate the core clock machinery in patients with bipolar illness. We examined the rhythmic expression patterns of core clock genes (BMAL1, PER1, PER2, REV-ERBa, DEC2, DBP) in fibroblasts from 12 bipolar patients and 12 healthy controls. Although we did not detect differences in the circadian period between bipolar patients and controls, the amplitude of rhythmic expression for BMAL1, REVERBa and DBP, as well as the overall mRNA expression level for DEC2 and DBP was reduced in fibroblasts from bipolar patients. Bonferroni's correction for multiple comparisons still resulted in significantly reduced DBP expression level, and trends toward reduced overall expression level of DEC2 and circadian amplitude of BMAL1, in fibroblasts from bipolar patients. We next examined an expanded cohort of 18 bipolar patients and 35 healthy controls for mRNA expression levels of four kinases (CKId, CKIe, GSK3a and GSK3b) and the protein and phosphorylation levels of two of them (GSK3a and GSK3b). We did not detect differences in steady-state mRNA levels or protein levels of these kinases between bipolar patients and controls, but the level of GSK3b phosphorylation was significantly reduced in bipolar patients within an Old Order Amish bipolar kindred. Our results suggest that the reduced amplitudes and overall expression levels of circadian genes, and the decreased phosphorylation level of GSK3b may lead to dysregulation of downstream genes, which could explain some pathological features of bipolar disorder.

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Human casein kinase Iδ phosphorylation of human circadian clock proteins period 1 and 2

Cited by 138 publications

References 26 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

Role of Phosphorylation in the Mammalian Circadian Clock

Assessment of circadian function in fibroblasts of patients with bipolar disorder

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