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Science 311 (5763): 1002-1005

Copyright © 2006 by the American Association for the Advancement of Science

Nuclear Receptor Rev-erb{alpha} Is a Critical Lithium-Sensitive Component of the Circadian Clock

Lei Yin,1 Jing Wang,1 Peter S. Klein,2 Mitchell A. Lazar1*

Abstract: Lithium is commonly used to treat bipolar disorder, which is associated with altered circadian rhythm. Lithium is a potent inhibitor of glycogen synthase kinase 3 (GSK3), which regulates circadian rhythm in several organisms. In experiments with cultured cells, we show here that GSK3ß phosphorylates and stabilizes the orphan nuclear receptor Rev-erb{alpha}, a negative component of the circadian clock. Lithium treatment of cells leads to rapid proteasomal degradation of Rev-erb{alpha} and activation of clock gene Bmal1. A form of Rev-erb{alpha} that is insensitive to lithium interferes with the expression of circadian genes. Control of Rev-erb{alpha} protein stability is thus a critical component of the peripheral clock and a biological target of lithium therapy.

1 Division of Endocrinology, Diabetes, and Metabolism, and University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA.
2 Division of Hematology and Oncology, Department of Medicine, and the Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA.

* To whom correspondence should be addressed. E-mail: lazar{at}mail.med.upenn.edu

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