Lee C, Weaver DR, Reppert SM. Direct association between mouse PERIOD and CKI is critical for a functioning circadian clock. Mol Cell Biol 24: 584-594

Department of Neurobiology, LRB-728, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 02/2004; 24(2):584-94. DOI: 10.1128/MCB.24.2.584-594.2004
Source: PubMed


The mPER1 and mPER2 proteins have important roles in the circadian clock mechanism, whereas mPER3 is expendable. Here we examine
the posttranslational regulation of mPER3 in vivo in mouse liver and compare it to the other mPER proteins to define the salient
features required for clock function. Like mPER1 and mPER2, mPER3 is phosphorylated, changes cellular location, and interacts
with other clock proteins in a time-dependent manner. Consistent with behavioral data from mPer2/3 and mPer1/3 double-mutant mice, either mPER1 or mPER2 alone can sustain rhythmic posttranslational events. However, mPER3 is unable to
sustain molecular rhythmicity in mPer1/2 double-mutant mice. Indeed, mPER3 is always cytoplasmic and is not phosphorylated in the livers of mPer1-deficient mice, suggesting that mPER3 is regulated by mPER1 at a posttranslational level. In vitro studies with chimeric
proteins suggest that the inability of mPER3 to support circadian clock function results in part from lack of direct and stable
interaction with casein kinase Iε (CKIε). We thus propose that the CKIε-binding domain is critical not only for mPER phosphorylation
but also for a functioning circadian clock.

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    • "It is clear that polymorphisms in hPer3 can influence diurnal preference, but this is likely related to an effect on sleep homeostasis rather than circadian function per se (Viola et al., 2007). Consistent with the biochemical evidence that PER3 is unable directly to interact with CK1ϵ (Lee et al., 2004), our in vivo and in vitro results exclude endogenous PER3 both as an essential circadian factor in the SCN and as a mediator of CK1ϵTau actions. "
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    ABSTRACT: The suprachiasmatic nucleus (SCN) of the hypothalamus is the principal circadian pacemaker in mammals, coordinating daily metabolic and physiological rhythms with the cycle of sleep and wakefulness. SCN neurons define circadian time via an auto-regulatory feedback loop in which the activation of Period (Per) and Cryptochrome genes is periodically suppressed by their own protein products. Casein kinase 1 (CK1) enzymes have a critical role in circadian pacemaking because they phosphorylate PER proteins and thereby direct their proteasomal degradation. In human pedigrees, individual mutations in either hCK1 or hPER2 lead to advanced sleep phase disorders, whereas in rodents, the Tau mutation of CK1 epsilon (CK1ε (Tau) ) accelerates rest-activity cycles and shortens the period of the SCN molecular pacemaker. Biochemical analyses of recombinant PER proteins in cultured cells and endogenous proteins in peripheral tissues have identified PER1 and PER2, but not PER3, as direct substrates of CK1ε. The purpose of this study, therefore, was to determine the relative contributions of endogenous PER proteins to the period-accelerating effects of CK1ε (Tau) , both in vivo and in vitro. CK1ε (Tau) mice were mated onto Per1-, Per2-, and Per1-Per2 (Per1/2) double-null backgrounds, in all cases carrying the Per1-luciferase bioluminescent circadian reporter gene. Mice lacking both PER1 and PER2 were behaviorally arrhythmic, confirming the inadequacy of PER3 as a circadian factor. Individual loss of either PER1 or PER2 had no significant effect on the circadian period or quality of wheel-running behavior, and CK1ε (Tau) accelerated behavioral rhythms in both Per1- and Per2-null mice. CK1ε (Tau) also accelerated in vitro molecular pacemaking in SCN lacking either PER1 or PER2, with a greater effect in PER2-dependent (i.e., Per1-null) SCN than in PER1-dependent slices. In double-null slices, some SCN were arrhythmic, whereas others exhibited transient rhythms, which trended nonsignificantly toward a shorter period. Both short-period and long-period rhythms could be identified in individual SCN neurons imaged by charge-coupled device camera. CK1ε (Tau) had no effect, however, on SCN-level or individual neuronal rhythms in the absence of PER1 and PER2. Thus, the CK1ε (Tau) allele has divergent actions, acting via both endogenous PER1 and PER2, but not PER3 protein, to mediate its circadian actions in vivo. Moreover, PER-independent cellular oscillations may contribute to pacemaking, but they are unstable and imprecise, and are not affected by the Tau mutation.
    Full-text · Article · Apr 2014 · Journal of Biological Rhythms
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    • "Nighttime, when mice were under light–dark conditions, is indicated by a black bar on the abscissa. Neurogenetics of food anticipation 1677 (Lowrey et al., 2000; Lee et al., 2004). "
    Dataset: EJN2009-30a

    Full-text · Dataset · Oct 2012
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    • "This mechanism of regulated transcription and inhibition of different components of the circadian oscillator makes the clock mechanism a robust and entrainable oscillator [9] [10]. This balance between transcription and translation of certain genes keeps the core clock strictly regulated and also plastic, contributing to circadian rhythmicity [11] [12]. The suprachiasmatic nucleus (SCN), located within the brain of mammals, is considered the center of the circadian clock in the body [6]. "
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    ABSTRACT: The major pathways involving nutrient and energy metabolism including cellular homeostasis are profoundly impacted by the circadian clock, which orchestrates diurnal rhythms in physiology and behavior. While the links between circadian and metabolic rhythms are unclear, recent studies imply a close link between the two with one feeding back on the other. In this discussion, we present the hypothesis that circadian clocks likely contribute to cellular homeostasis, especially proteostasis, through regulation of metabolic rhythms, which in turn feed-back on circadian oscillators. The disruption of circadian clocks leads to altered metabolic rhythms and metabolic disease states as a result of altered cellular homeostasis.
    Full-text · Article · Apr 2012 · Medical Hypotheses
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