Posttranslational mechanisms regulate the mammalian circadian clock.
We have examined posttranslational regulation of clock proteins in mouse liver in vivo. The mouse PERIOD proteins (mPER1 and mPER2), CLOCK, and BMAL1 undergo robust circadian changes in phosphorylation. These proteins, the cryptochromes (mCRY1 and mCRY2), and casein kinase I epsilon (CKIepsilon) form multimeric complexes that are bound to DNA during negative transcriptional feedback. CLOCK:BMAL1 heterodimers remain bound to DNA over the circadian cycle. The temporal increase in mPER abundance controls the negative feedback interactions. Analysis of clock proteins in mCRY-deficient mice shows that the mCRYs are necessary for stabilizing phosphorylated mPER2 and for the nuclear accumulation of mPER1, mPER2, and CKIepsilon. We also provide in vivo evidence that casein kinase I delta is a second clock relevant kinase.
Lee
C
C
Department of Neurobiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Etchegaray
J P
JP
Cagampang
F R
FR
Loudon
A S
AS
Reppert
S M
SM
D000818:Animals; D047388:Casein Kinases; D018797:Cell Cycle Proteins; D002940:Circadian Rhythm / Q000502:physiology*; D008099:Liver / Q000502:physiology; D051379:Mice; D009687:Nuclear Proteins / Q000502:physiology*; D056950:Period Circadian Proteins; D010766:Phosphorylation; D011494:Protein Kinases; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D014157:Transcription Factors
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D014157:Transcription Factors; D011494:Protein Kinases; D047388:Casein Kinases