Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon.
The molecular oscillator that keeps circadian time is generated by a negative feedback loop. Nuclear entry of circadian regulatory proteins that inhibit transcription from E-box-containing promoters appears to be a critical component of this loop in both Drosophila and mammals. The Drosophila double-time gene product, a casein kinase I epsilon (CKIepsilon) homolog, has been reported to interact with dPER and regulate circadian cycle length. We find that mammalian CKIepsilon binds to and phosphorylates the murine circadian regulator mPER1. Unlike both dPER and mPER2, mPER1 expressed alone in HEK 293 cells is predominantly a nuclear protein. Two distinct mechanisms appear to retard mPER1 nuclear entry. First, coexpression of mPER2 leads to mPER1-mPER2 heterodimer formation and cytoplasmic colocalization. Second, coexpression of CKIepsilon leads to masking of the mPER1 nuclear localization signal and phosphorylation-dependent cytoplasmic retention of both proteins. CKIepsilon may regulate mammalian circadian rhythm by controlling the rate at which mPER1 enters the nucleus.
Vielhaber
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E
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City 84132, USA.
Eide
E
E
Rivers
A
A
Gao
Z H
ZH
Virshup
D M
DM
D000595:Amino Acid Sequence; D001665:Binding Sites; D047388:Casein Kinases; D018797:Cell Cycle Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002940:Circadian Rhythm / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056950:Period Circadian Proteins; D010766:Phosphorylation; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D007527:Isoenzymes; D009687:Nuclear Proteins; C539022:PER1 protein, human; D056950:Period Circadian Proteins; D011994:Recombinant Proteins; D011494:Protein Kinases; D047388:Casein Kinases