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Molecular and Cellular Biology, July 2000, p. 4888-4899, Vol. 20, No. 13
Department of Oncological Sciences, Huntsman
Cancer Institute,1 and Division of
Hematology/Oncology, Department of
Pediatrics,2 University of Utah, Salt Lake City,
Utah
Received 15 December 1999/Returned for modification 1 February
2000/Accepted 29 March 2000
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
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Nuclear Entry of the Circadian Regulator mPER1 Is
Controlled by Mammalian Casein Kinase I
(CKI
) homolog,
has been reported to interact with dPER and regulate circadian cycle
length. We find that mammalian CKI
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 CKI
leads to
masking of the mPER1 nuclear localization signal and
phosphorylation-dependent cytoplasmic retention of both
proteins. CKI
may regulate mammalian circadian rhythm by
controlling the rate at which mPER1 enters the nucleus.
*
Corresponding author. Mailing address: Department of
Oncological Sciences, 5C334 School of Medicine, 50 N. Medical Dr.,
University of Utah, Salt Lake City, UT 84132. Phone: (801) 585-3408. Fax: (801) 585-0900. E-mail:
david.virshup{at}hci.utah.edu.
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