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J. Biol. Chem., Vol. 280, Issue 29, 26863-26872, July 22, 2005

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SCF^-TRCP Controls Clock-dependent Transcription via Casein Kinase 1-dependent Degradation of the Mammalian Period-1 (Per1) Proteinm^*

Takahiro Shirogane, Jianping Jin, Xiaolu L. Ang, and J. Wade Harper¶

From the Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115

Circadian rhythms are controlled by the periodic accumulation of Period proteins, which act as transcriptional repressors of Clock-dependent genes. Period genes are themselves Clock targets, thereby establishing a negative transcriptional feedback circuit controlling circadian periodicity. Previous data have implicated the CK1 isolog Doubletime (Dbt) and the F-box protein Slimb in the regulation of Drosophila Period (Per) through an unknown mechanism. In this work, we have identified components of the machinery involved in regulating the abundance of human Per1 in tissue culture cells. CK1 and CK12 were found to bind to Per1 and to promote its degradation in an in vivo degradation assay. Per1 turnover was blocked by a dominant negative version of the Cul1 protein, a component of the SCF (Skp1-Cul1-F-box protein) ubiquitin ligase. We screened a panel of F-box proteins for those that would associate with Per1 in a CK1-dependent manner, and we identified -TRCP1 and -TRCP2, isologs of the Drosophila Slimb protein. RNA interference against -transducin repeat-containing protein (-TRCP) stabilizes endogenous and exogenous Per1. -TRCP associates with sequences near the N terminus of Per1 in a region distinct from the previously characterized CK1-binding site. -TRCP and CK1 promote Per1 ubiquitination in vitro. Finally, RNA interference against -TRCP greatly decreases Clock-dependent gene expression in tissue culture cells, indicating that -TRCP controls endogenous Per1 activity and the circadian clock by directly targeting Per1 for degradation.

Received for publication, March 15, 2005 , and in revised form, May 16, 2005.

^* This work was supported in part by National Institutes of Health Grant AG11085 (to J. W. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Japanese Society for Science.

Supported by a Department of Defense post-doctoral fellowship in breast cancer.

^¶ To whom correspondence should be addressed: Dept. of Pathology, Harvard Medical School, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: 617-432-6590; Fax: 617-432-6591; E-mail: wade_harper{at}hms.harvard.edu.

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