Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Site Tools

  • AAAS
  • Subscribe
  • Feedback

Site Search

Search Advanced

Science 17 February 2006:
Vol. 311. no. 5763, pp. 1002 - 1005
DOI: 10.1126/science.1121613

Reports

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*

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

Read the Full Text



THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Rev-erb{alpha}2 mRNA Encodes a Stable Protein with a Potential Role in Circadian Clock Regulation.
J. Rambaud, G. Triqueneaux, I. Masse, B. Staels, V. Laudet, and G. Benoit (2009)
Mol. Endocrinol. 23, 630-639
   Abstract »    Full Text »    PDF »
A chemical biology approach reveals period shortening of the mammalian circadian clock by specific inhibition of GSK-3{beta}.
T. Hirota, W. G. Lewis, A. C. Liu, J. W. Lee, P. G. Schultz, and S. A. Kay (2008)
PNAS 105, 20746-20751
   Abstract »    Full Text »    PDF »
Minireview: The Nuclear Hormone Receptor Family Round the Clock.
M. Teboul, F. Guillaumond, A. Grechez-Cassiau, and F. Delaunay (2008)
Mol. Endocrinol. 22, 2573-2582
   Abstract »    Full Text »    PDF »
Ligand modulation of REV-ERB{alpha} function resets the peripheral circadian clock in a phasic manner.
Q. J. Meng, A. McMaster, S. Beesley, W. Q. Lu, J. Gibbs, D. Parks, J. Collins, S. Farrow, R. Donn, D. Ray, et al. (2008)
J. Cell Sci. 121, 3629-3635
   Abstract »    Full Text »    PDF »
Looking at Lithium: Molecular Moods and Complex Behaviour.
J.-M. Beaulieu and M. G. Caron (2008)
Mol. Interv. 8, 230-241
   Abstract »    Full Text »    PDF »
Circadian Phenotype in Patients with the Co-Morbid Alcohol Use and Bipolar Disorders.
T. Hatonen, S. Forsblom, T. Kieseppa, J. Lonnqvist, and T. Partonen (2008)
Alcohol Alcohol. 43, 564-568
   Abstract »    Full Text »    PDF »
Sleep Disturbance in Bipolar Disorder: Therapeutic Implications.
D. T. Plante and J. W. Winkelman (2008)
Am J Psychiatry 165, 830-843
   Abstract »    Full Text »    PDF »
Nuclear Hormone Receptors for Heme: REV-ERB{alpha} and REV-ERB{beta} Are Ligand-Regulated Components of the Mammalian Clock.
T. P. Burris (2008)
Mol. Endocrinol. 22, 1509-1520
   Abstract »    Full Text »    PDF »
The nuclear receptors Rev-erbs and RORs integrate circadian rhythms and metabolism.
H. Duez and B. Staels (2008)
Diabetes and Vascular Disease Research 5, 82-88
   Abstract »    PDF »
Bifunctional Role of Rev-erb{alpha} in Adipocyte Differentiation.
J. Wang and M. A. Lazar (2008)
Mol. Cell. Biol. 28, 2213-2220
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
Circadian Organization oftau Mutant Hamsters: Aftereffects and Splitting.
E. L. Bittman, M. K. Costello, and J. McKinley Brewer (2007)
J Biol Rhythms 22, 425-431
   Abstract »    PDF »
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
   Abstract »    Full Text »    PDF »
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
   Abstract »    Full Text »    PDF »
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.
M.-H. Liang and D.-M. Chuang (2007)
J. Biol. Chem. 282, 3904-3917
   Abstract »    Full Text »    PDF »
Glycogen Synthase Kinase-3 Phosphorylates CdGAP at a Consensus ERK 1 Regulatory Site.
E. I. Danek, J. Tcherkezian, I. Triki, M. Meriane, and N. Lamarche-Vane (2007)
J. Biol. Chem. 282, 3624-3631
   Abstract »    Full Text »    PDF »
Role of Phosphorylation in the Mammalian Circadian Clock.
K. Vanselow and A. Kramer (2007)
Cold Spring Harb Symp Quant Biol 72, 167-176
   Abstract »    PDF »
Nuclear Receptors, Metabolism, and the Circadian Clock.
X. Yang, K. A. Lamia, and R. M. Evans (2007)
Cold Spring Harb Symp Quant Biol 72, 387-394
   Abstract »    PDF »
Role for the Clock Gene in Bipolar Disorder.
C. A. McClung (2007)
Cold Spring Harb Symp Quant Biol 72, 637-644
   Abstract »    PDF »
Systems Biology of Circadian Rhythms: An Outlook.
L. De Haro and S. Panda (2006)
J Biol Rhythms 21, 507-518
   Abstract »    PDF »
The Orphan Nuclear Receptor Rev-erb{alpha} Regulates Circadian Expression of Plasminogen Activator Inhibitor Type 1.
J. Wang, L. Yin, and M. A. Lazar (2006)
J. Biol. Chem. 281, 33842-33848
   Abstract »    Full Text »    PDF »
Lithium Leads to an Increased FRQ Protein Stability and to a Partial Loss of Temperature Compensation in the Neurospora Circadian Clock.
I. W. Jolma, G. Falkeid, M. Bamerni, and P. Ruoff (2006)
J Biol Rhythms 21, 327-334
   Abstract »    PDF »
Wnt signaling: is the party in the nucleus?.
K. Willert and K. A. Jones (2006)
Genes & Dev. 20, 1394-1404
   Abstract »    Full Text »    PDF »



To Advertise     Find Products


Science. ISSN 0036-8075 (print), 1095-9203 (online)