Serum stimulation caused daily oscillations of human PER1 protein (hPER1) and the apparent molecular mass of hPER1 changed. Inhibitor studies indicated that the casein kinase I family. phosphorylated hPER1 and increased the apparent molecular mass of hPER1. The inhibition of hPER1 Phosphorylation by CKI-7, a casein kinase I inhibitor, disturbed hPER1 degradation, delayed the nuclear entry of hPER1 and allowed it to persist for longer in the nucleus. Furthermore, proteasome inhibitors specifically blocked hPER1 degradation, while leptomycin B, an inhibitor of nuclear export, did not alter the degradation state of hPER1 protein. These findings indicate that circadian hPER1 degradation through a proteasomal pathway can be regulated through phosphorylation by casein kinase I, but not by subcellular localization.