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Molecular and Cellular Biology, July 2000, p. 4888-4899, Vol. 20, No. 13
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 epsilon

Erica Vielhaber,1 Erik Eide,1 Ann Rivers,1 Zhong-Hua Gao,1 and David M. Virshup1,2,*

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 varepsilon  (CKIvarepsilon ) homolog, has been reported to interact with dPER and regulate circadian cycle length. We find that mammalian CKIvarepsilon 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 CKIvarepsilon leads to masking of the mPER1 nuclear localization signal and phosphorylation-dependent cytoplasmic retention of both proteins. CKIvarepsilon 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.

Molecular and Cellular Biology, July 2000, p. 4888-4899, Vol. 20, No. 13
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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