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Molecular and Cellular Biology, January 2004, p. 584-594, Vol. 24, No. 2
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.2.584-594.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Direct Association between Mouse PERIOD and CKI{varepsilon} Is Critical for a Functioning Circadian Clock

Choogon Lee,{dagger} David R. Weaver, and Steven M. Reppert*

Department of Neurobiology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Received 4 September 2003/ Returned for modification 19 September 2003/ Accepted 7 October 2003

The mPER1 and mPER2 proteins have important roles in the circadian clock mechanism, whereas mPER3 is expendable. Here we examine the posttranslational regulation of mPER3 in vivo in mouse liver and compare it to the other mPER proteins to define the salient features required for clock function. Like mPER1 and mPER2, mPER3 is phosphorylated, changes cellular location, and interacts with other clock proteins in a time-dependent manner. Consistent with behavioral data from mPer2/3 and mPer1/3 double-mutant mice, either mPER1 or mPER2 alone can sustain rhythmic posttranslational events. However, mPER3 is unable to sustain molecular rhythmicity in mPer1/2 double-mutant mice. Indeed, mPER3 is always cytoplasmic and is not phosphorylated in the livers of mPer1-deficient mice, suggesting that mPER3 is regulated by mPER1 at a posttranslational level. In vitro studies with chimeric proteins suggest that the inability of mPER3 to support circadian clock function results in part from lack of direct and stable interaction with casein kinase I{varepsilon} (CKI{varepsilon}). We thus propose that the CKI{varepsilon}-binding domain is critical not only for mPER phosphorylation but also for a functioning circadian clock.

* Corresponding author. Mailing address: Department of Neurobiology, LRB-728, University of Massachusetts Medical School, 364 Plantation St., Worcester, MA 01605. Phone: (508) 856-6148. Fax: (508) 856-6266. E-mail: Steven.Reppert{at}umassmed.edu.

{dagger} Present address: Department of Biological Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306.

Molecular and Cellular Biology, January 2004, p. 584-594, Vol. 24, No. 2
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.2.584-594.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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