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 negati ve feedback loop. Nuclear entry of circadian regulatory proteins that inhib it transcription from E-box-containing promoters appears to be a critical c omponent of this loop in both Drosophila and mammals. The Drosophila double -time gene product, a casein kinase I epsilon (CKI epsilon) homolog, has be en reported to interact with dPER and regulate circadian cycle length. We f ind that mammalian CKI epsilon binds to and phosphorylates the murine circa dian regulator mPER1. Unlike both dPER and mPER2, mPER1 expressed alone in HEK 293 cells is predominantly a nuclear protein. Two distinct mechanisms a ppear to retard mPER1 nuclear entry. First, coexpression of mPER2 leads to mPER1-mPER2 heterodimer formation and cytoplasmic colocalization. Second, c oexpression of CKI epsilon leads to masking of the mPER1 nuclear localizati on signal and phosphorylation-dependent cytoplasmic retention of both prote ins. CKI epsilon may regulate mammalian circadian rhythm by controlling the rate at which mPER1 enters the nucleus.