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Nuclear Receptor Rev-erb Is a Critical Lithium-Sensitive Component of the Circadian Clock
Lei Yin,1Jing Wang,1Peter S. Klein,2Mitchell A. Lazar1*
Lithium is commonly used to treat bipolar disorder, which isassociated with altered circadian rhythm. Lithium is a potentinhibitor of glycogen synthase kinase 3 (GSK3), which regulatescircadian rhythm in several organisms. In experiments with culturedcells, we show here that GSK3ß phosphorylates andstabilizes the orphan nuclear receptor Rev-erb, a negative componentof the circadian clock. Lithium treatment of cells leads torapid proteasomal degradation of Rev-erb and activation of clockgene Bmal1. A form of Rev-erb that is insensitive to lithiuminterferes with the expression of circadian genes. Control ofRev-erb protein stability is thus a critical component of theperipheral 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
Rev-erb{alpha}, a Heme Sensor That Coordinates Metabolic and Circadian Pathways.
L. Yin, N. Wu, J. C. Curtin, M. Qatanani, N. R. Szwergold, R. A. Reid, G. M. Waitt, D. J. Parks, K. H. Pearce, G. B. Wisely, et al. (2007)
Science
318, 1786-1789
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E. L. Bittman, M. K. Costello, and J. McKinley Brewer (2007)
J Biol Rhythms
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Two differentially active alternative promoters control the expression of the zebrafish orphan nuclear receptor gene Rev-erb{alpha}.
T. Kakizawa, S.-i. Nishio, G. Triqueneaux, S. Bertrand, J. Rambaud, and V. Laudet (2007)
J. Mol. Endocrinol.
38, 555-568
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Disturbed Diurnal Rhythm Alters Gene Expression and Exacerbates Cardiovascular Disease With Rescue by Resynchronization.
T. A. Martino, N. Tata, D. D. Belsham, J. Chalmers, M. Straume, P. Lee, H. Pribiag, N. Khaper, P. P. Liu, F. Dawood, et al. (2007)
Hypertension
49, 1104-1113
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Inhibition of GSK3 Promotes Replication and Survival of Pancreatic Beta Cells.
R. Mussmann, M. Geese, F. Harder, S. Kegel, U. Andag, A. Lomow, U. Burk, D. Onichtchouk, C. Dohrmann, and M. Austen (2007)
J. Biol. Chem.
282, 12030-12037
|Abstract »|Full Text »|PDF »
Regulation and Function of Glycogen Synthase Kinase-3 Isoforms in Neuronal Survival.
Is a Critical Lithium-Sensitive Component of the Circadian Clock
, a negative component of the circadian clock. Lithium treatment of cells leads to rapid proteasomal degradation of Rev-erb
