A role for glycogen synthase kinase-3beta in the mammalian circadian clock.
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.
Clock Cell Biology Research Group, Institute for Biological Resource and Function, National Institute of Advanced Industrial Science and Technology, Higashi, Tsukuba, Ibaraki, Japan.
Chisato
C
Iitaka
Koyomi
K
Miyazaki
Toshihiro
T
Akaike
Norio
N
Ishida
D056930:ARNTL Transcription Factors; D021581:Active Transport, Cell Nucleus; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001665:Binding Sites; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000737:chemistry / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008813:Mice, Inbred ICR; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056950:Period Circadian Proteins; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D009687:Nuclear Proteins; D056950:Period Circadian Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; C538961:Bmal1 protein, mouse; C513312:Per2 protein, mouse; C000605507:Gsk3b protein, mouse