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: 5.04). 02/2004; 24(2):584-94. DOI: 10.1128/MCB.24.2.584-594.2004
Source: PubMed

ABSTRACT 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 Iepsilon (CKIepsilon). We thus propose that the CKIepsilon-binding domain is critical not only for mPER phosphorylation but also for a functioning circadian clock.

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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
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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.
    Medical Hypotheses 04/2012; 79(1):17-24. DOI:10.1016/j.mehy.2012.03.023 · 1.07 Impact Factor
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    • "There are several contradictory reports regarding the nuclear import of Per1 and Per3 proteins. While a few reports suggested that the nuclear import of Per1 requires dimerization with Per3, other reports have suggested that Per1 is required for the nuclear import of Per3 [14] [15] [16]. Thus, the protein that is more critical for the nuclear import and checkpoint activation is still largely controversial and remains to be solved. "
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    ABSTRACT: PER3 is a member of the PERIOD genes, but does not play essential roles in the circadian clock. Depletion of Per3 by siRNA almost completely abolished activation of checkpoint kinase 2 (Chk2) after inducing DNA damage in human cells. In addition, Per3 physically interacted with ATM and Chk2. Per3 overexpression induced Chk2 activation in the absence of exogenous DNA damage, and this activation depended on ATM. Per3 overexpression also led to the inhibition of cell proliferation and apoptotic cell death. These combined results suggest that Per3 is a checkpoint protein that plays important roles in checkpoint activation, cell proliferation and apoptosis.
    FEBS letters 11/2010; 584(23):4731-4. DOI:10.1016/j.febslet.2010.11.003 · 3.34 Impact Factor
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