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Molecular and Cellular Biology, March 2002, p. 1693-1703, Vol. 22, No. 6
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.6.1693-1703.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Control of Intracellular Dynamics of Mammalian Period Proteins by Casein Kinase I (CKI) and CKI in Cultured Cells

Department of Biophysics, Graduate School of Science,¹ Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan²

Received 25 July 2001/ Returned for modification 20 August 2001/ Accepted 4 December 2001

Recent studies have shown that casein kinase I (CKI) is an essential regulator of the mammalian circadian clock. However, the detailed mechanisms by which CKI regulates each component of the circadian negative-feedback loop have not been fully defined. We show here that mPer proteins, negative limbs of the autoregulatory loop, are specific substrates for CKI and CKI. The CKI phosphorylation of mPer1 and mPer3 proteins results in their rapid degradation, which is dependent on the ubiquitin-proteasome pathway. Moreover, CKI and CKI are able to induce nuclear translocation of mPer3, which requires its nuclear localization signal. The mutation in potential phosphorylation sites on mPer3 decreased the extent of both nuclear translocation and degradation of mPer3 that are stimulated by CKI. CKI and CKI affected the inhibitory effect of mPer proteins on the transcriptional activity of BMAL1-CLOCK, but the inhibitory effect of mCry proteins on the activity of BMAL1-CLOCK was unaffected. These results suggest that CKI and CKI regulate the mammalian circadian autoregulatory loop by controlling both protein turnover and subcellular localization of mPer proteins.

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