A Role for Glycogen Synthase Kinase-3β in the Mammalian Circadian Clock*
- ‡Clock Cell Biology Research Group, Institute for Biological Resource and Function, National Institute of Advanced Industrial Science and Technology, Central 6, 1-1-1, Higashi, Tsukuba, Ibaraki 305-8566, Japan, the §Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-Cho, Midori-Ku, Yokohama, Kanagawa 226-8501, Japan, and the ¶Institute of Applied Biochemistry, University of Tsukuba, Tsukuba, Ibaraki 305-8502, Japan
- ↵∥ To whom correspondence should be addressed. Tel.: 81-29-861-6053; Fax: 81-29-861-9499; E-mail: n.ishida{at}aist.go.jp.
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.
- Received March 31, 2005.
- Revision received June 17, 2005.
- The American Society for Biochemistry and Molecular Biology, Inc.
