A role for glycogen synthase kinase-3beta in the mammalian circadian clock.
ABSTRACT The Drosophila shaggy gene product is a mammalian glycogen synthase kinase-3beta (GSK-3beta) homologue that contributes to the circadian clock of the Drosophila through TIMELESS phosphorylation, and it regulates nuclear translocation of the PERIOD/TIMELESS heterodimer. We found that mammalian GSK-3beta is expressed in the suprachiasmatic nucleus and liver of mice and that GSK-3beta phosphorylation exhibits robust circadian oscillation. Rhythmic GSK-3beta phosphorylation is also observed in serum-shocked NIH3T3 cells. Exposing serum-shocked NIH3T3 cells to lithium chloride, a specific inhibitor of GSK-3beta, increases GSK-3beta phosphorylation and delays the phase of rhythmic clock gene expression. On the other hand, GSK-3beta overexpression advances the phase of clock gene expression. We also found that GSK-3beta interacts with PERIOD2 (PER2) in vitro and in vivo. Recombinant GSK-3beta can phosphorylate PER2 in vitro. GSK-3beta promotes the nuclear translocation of PER2 in COS1 cells. The present data suggest that GSK-3beta plays important roles in mammalian circadian clock.
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ABSTRACT: The dominant genetic and environmental causes of mood disorders and schizophrenia have not been forthcoming, so alternative approaches are required to elucidate the mechanisms underlying these diseases and to develop improved treatments for use in the clinic. Pharmacological evidence implicates glycogen synthase kinase 3 (GSK3) as a key target of current therapeutics, and this is well supported by genetic studies in animal models. Several upstream regulators of GSK3 are also genetically associated with mood disorders and schizophrenia, further suggesting convergence on GSK3 signalling. Whereas pathways upstream of GSK3 are being elucidated, relatively little progress has been made in identifying targets downstream of GSK3 that mediate its functional effects. This is important, because these substrates themselves could become next-generation therapeutic targets that are more potent and specific than current therapeutics targeting GSK3. Here, a few likely candidates and their connection to mood disorders and schizophrenia are discussed.FEBS Journal 11/2013; 280(21). · 3.99 Impact Factor
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ABSTRACT: Circadian (~24hr) clocks control daily rhythms in metabolism, physiology and behavior in animals, plants and microbes. In Drosophila, these clocks keep circadian time via transcriptional feedback loops in which CLOCK-CYCLE (CLK-CYC) initiates transcription of period (per) and timeless (tim), accumulating levels of PER and TIM feed back to inhibit CLK-CYC, and degradation of PER and TIM allows CLK-CYC to initate the next cycle of transcription. The timing of key events in this feedback loop are controlled by, or coincide with, rhythms in PER and CLK phosphorylation, where PER and CLK phosphorylation is high during transcriptional repression. PER phosphorylation at specific sites controls its subcellular localization, activity and stability, but comparatively little is known about the identity and function of CLK phosphorylation sites. Here we identify eight CLK phosphorylation sites via mass spectrometry and determine how phosphorylation at these sites impacts behavioral and molecular rhythms by transgenic rescue of a new Clk null mutant. Eliminating phosphorylation at four of these sites accelerates the feedback loop to shorten circadian period, whereas loss of CLK phosphorylation at serine 859 increases CLK activity, thereby increasing PER levels and accelerating transcriptional repression. These results demonstrate that CLK phosphorylation influences circadian period by regulating CLK activity and progression through the feedback loop.Journal of Biological Chemistry 05/2014; · 4.60 Impact Factor
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ABSTRACT: Disturbed sleep-wake cycle and circadian rhythmicity are associated with cancer, but the underlying mechanisms are unknown. Employing a tissue-isolated human breast xenograft tumor nude rat model, we observed that glycogen synthase kinase 3β (GSK3β), an enzyme critical in metabolism and cell proliferation/survival, exhibits a circadian rhythm of phosphorylation in human breast tumors. Exposure to light-at-night suppresses the nocturnal pineal melatonin synthesis, disrupting the circadian rhythm of GSK3β phosphorylation. Melatonin activates GSK3β by inhibiting the serine-threonine kinase Akt phosphorylation, inducing β-catenin degradation and inhibiting epithelial-to-mesenchymal transition, a fundamental process underlying cancer metastasis. Thus, chronic circadian disruption by light-at-night via occupational exposure or age-related sleep disturbances may contribute to cancer incidence and the metastatic spread of breast cancer by inhibiting GSK3β activity and driving epithelial-to-mesenchymal transition in breast cancer patients.Molecular Endocrinology 11/2012; 26(11):1808-1820. · 4.20 Impact Factor