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.
Iitaka
Chisato
C
Clock Cell Biology Research Group, Institute for Biological Resource and Function, National Institute of Advanced Industrial Science and Technology, Higashi, Tsukuba, Ibaraki, Japan.
Miyazaki
Koyomi
K
Akaike
Toshihiro
T
Ishida
Norio
N
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