A Role for Glycogen Synthase Kinase-3β in the 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. [ABSTRACT FROM AUTHOR]