A Role for Glycogen Synthase Kinase-3β in the Mammalian Circadian Clock

Abstract

The Drosophila shaggy gene product is a mammalian glycogen synthase kinase-3β (GSK-3β) 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-3β is expressed in the suprachiasmatic nucleus and liver of mice and that GSK-3β phosphorylation exhibits robust circadian oscillation. Rhythmic GSK-3β phosphorylation is also observed in serum-shocked NIH3T3 cells. Exposing serum-shocked NIH3T3 cells to lithium chloride, a specific inhibitor of GSK-3β, increases GSK-3β phosphorylation and delays the phase of rhythmic clock gene expression. On the other hand, GSK-3β overexpression advances the phase of clock gene expression. We also found that GSK-3β interacts with PERIOD2 (PER2) in vitro and in vivo. Recombinant GSK-3β can phosphorylate PER2 in vitro. GSK-3β promotes the nuclear translocation of PER2 in COS1 cells. The present data suggest that GSK-3β plays important roles in mammalian circadian clock. The Drosophila shaggy gene product is a mammalian glycogen synthase kinase-3β (GSK-3β) 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-3β is expressed in the suprachiasmatic nucleus and liver of mice and that GSK-3β phosphorylation exhibits robust circadian oscillation. Rhythmic GSK-3β phosphorylation is also observed in serum-shocked NIH3T3 cells. Exposing serum-shocked NIH3T3 cells to lithium chloride, a specific inhibitor of GSK-3β, increases GSK-3β phosphorylation and delays the phase of rhythmic clock gene expression. On the other hand, GSK-3β overexpression advances the phase of clock gene expression. We also found that GSK-3β interacts with PERIOD2 (PER2) in vitro and in vivo. Recombinant GSK-3β can phosphorylate PER2 in vitro. GSK-3β promotes the nuclear translocation of PER2 in COS1 cells. The present data suggest that GSK-3β plays important roles in mammalian circadian clock. The behavior and physiology of most organisms show circadian, 24-h rhythmicity (1Pittendrigh C.S. Annu. Rev. Physiol. 1993; 55: 16-54Crossref PubMed Scopus (775) Google Scholar). Negative feedback loops in circadian genes are thought to control circadian rhythmicity in all organisms from bacteria to mammals (2Dunlap J.C. Cell. 1999; 96: 271-290Abstract Full Text Full Text PDF PubMed Scopus (2329) Google Scholar, 3Edery I. Physiol. Genomics. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, Annu. Rev. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). that control circadian to important circadian PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar). 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Cell. 1999; 96: 271-290Abstract Full Text Full Text PDF PubMed Scopus (2329) Google Scholar, 3Edery I. Physiol. Genomics. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, Annu. Rev. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). that control circadian to important circadian PubMed Scopus Google Scholar, Full Text Full Text PDF PubMed Scopus Google Scholar). The of the mammalian clock are the and that the PubMed Scopus Google Scholar, PubMed Scopus Google the the and PER2 and the and PubMed Scopus Google Scholar, Cell. 1999; 96: Full Text Full Text PDF PubMed Scopus Google Scholar, Cell. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The circadian in mammals is with the clock in the suprachiasmatic nucleus suprachiasmatic GSK-3β, glycogen synthase suprachiasmatic GSK-3β, glycogen synthase of the (2Dunlap J.C. Cell. 1999; 96: 271-290Abstract Full Text Full Text PDF PubMed Scopus (2329) Google Scholar). 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