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Control of Mammalian Circadian Rhythm by CKI-Regulated Proteasome-Mediated PER2 Degradation

Department of Oncological Sciences and the Center for Children, Huntsman Cancer Institute,¹ Division of Hematology/Oncology, Department of Pediatrics, University of Utah, Salt Lake City, Utah,⁴ Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan,² Aventis Pharmaceuticals, Bridgewater, New Jersey³

Received 1 October 2004/ Returned for modification 15 November 2004/ Accepted 28 December 2004

The mammalian circadian regulatory proteins PER1 and PER2 undergo a daily cycle of accumulation followed by phosphorylation and degradation. Although phosphorylation-regulated proteolysis of these inhibitors is postulated to be essential for the function of the clock, inhibition of this process has not yet been shown to alter mammalian circadian rhythm. We have developed a cell-based model of PER2 degradation. Murine PER2 (mPER2) hyperphosphorylation induced by the cell-permeable protein phosphatase inhibitor calyculin A is rapidly followed by ubiquitination and degradation by the 26S proteasome. Proteasome-mediated degradation is critically important in the circadian clock, as proteasome inhibitors cause a significant lengthening of the circadian period in Rat-1 cells. CKI (casein kinase I) has been postulated to prime PER2 for degradation. Supporting this idea, CKI inhibition also causes a significant lengthening of circadian period in synchronized Rat-1 cells. CKI inhibition also slows the degradation of PER2 in cells. CKI-mediated phosphorylation of PER2 recruits the ubiquitin ligase adapter protein ß-TrCP to a specific site, and dominant negative ß-TrCP blocks phosphorylation-dependent degradation of mPER2. These results provide a biochemical mechanism and functional relevance for the observed phosphorylation-degradation cycle of mammalian PER2. Cell culture-based biochemical assays combined with measurement of cell-based rhythm complement genetic studies to elucidate basic mechanisms controlling the mammalian clock.

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