Nuclear Receptor Rev-erbα Is a Critical Lithium-Sensitive Component of the Circadian Clock

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 GSK3β phosphorylates and stabilizes the orphan nuclear receptor Rev-erbα, a negative component of the circadian clock. Lithium treatment of cells leads to rapid proteasomal degradation of Rev-erbα and activation of clock gene Bmal1. A form of Rev-erbα that is insensitive to lithium interferes with the expression of circadian genes. Control of Rev-erbα protein stability is thus a critical component of the peripheral clock and a biological target of lithium therapy.

[1]  U. Schibler,et al.  A Serum Shock Induces Circadian Gene Expression in Mammalian Tissue Culture Cells , 1998, Cell.

[2]  G. Adelmant,et al.  A functional Rev-erb alpha responsive element located in the human Rev-erb alpha promoter mediates a repressing activity. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[3]  R. Matthews,et al.  Ants. , 1898, Science.

[4]  K. Fukunaga,et al.  Effect of lithium on the circadian rhythms of locomotor activity and glycogen synthase kinase‐3 protein expression in the mouse suprachiasmatic nuclei , 2004, The European journal of neuroscience.

[5]  M. W. Young,et al.  A Role for the Segment Polarity Gene shaggy/GSK-3 in the Drosophila Circadian Clock , 2001, Cell.

[6]  S. Reppert,et al.  Molecular analysis of mammalian circadian rhythms. , 2001, Annual review of physiology.

[7]  Steven A. Brown,et al.  Circadian gene expression in cultured cells. , 2005, Methods in enzymology.

[8]  David M. Raup,et al.  How Nature Works: The Science of Self-Organized Criticality , 1997 .

[9]  P. Taghert,et al.  Lithium- and Valproate-Induced Alterations in Circadian Locomotor Behavior in Drosophila , 2005, Neuropsychopharmacology.

[10]  H. Manji,et al.  Endophenotypes in bipolar disorder. , 2002, American journal of medical genetics.

[11]  D. Melton,et al.  A molecular mechanism for the effect of lithium on development. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Ping Zhu,et al.  Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells , 2001, The EMBO journal.

[13]  C. Phiel,et al.  Inhibitory Phosphorylation of Glycogen Synthase Kinase-3 (GSK-3) in Response to Lithium , 2003, Journal of Biological Chemistry.

[14]  J. Takahashi,et al.  Mammalian circadian biology: elucidating genome-wide levels of temporal organization. , 2004, Annual review of genomics and human genetics.

[15]  宁北芳,et al.  疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A , 2005 .

[16]  A. Serretti,et al.  A glycogen synthase kinase 3-β promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression , 2004, Neuroscience Letters.

[17]  Ueli Schibler,et al.  The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator , 2002, Cell.

[18]  K Kume,et al.  Interacting molecular loops in the mammalian circadian clock. , 2000, Science.

[19]  Sumio Sugano,et al.  A transcription factor response element for gene expression during circadian night , 2002, Nature.

[20]  M. Guenther,et al.  Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen* , 2001, The Journal of Biological Chemistry.

[21]  E. Eide,et al.  Casein kinase I in the mammalian circadian clock. , 2005, Methods in enzymology.

[22]  Steven A. Brown,et al.  The mammalian circadian timing system: from gene expression to physiology , 2004, Chromosoma.

[23]  Lei Yin,et al.  The orphan nuclear receptor Rev-erbalpha recruits the N-CoR/histone deacetylase 3 corepressor to regulate the circadian Bmal1 gene. , 2005, Molecular endocrinology.

[24]  E. Herzog,et al.  Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons , 2000, Neuroreport.

[25]  D. P. King,et al.  Role of the CLOCK protein in the mammalian circadian mechanism. , 1998, Science.

[26]  M. W. Young,et al.  Posttranscriptional and Posttranslational Regulation of Clock Genes , 2004, Journal of biological rhythms.

[27]  B. Doble,et al.  GSK-3: tricks of the trade for a multi-tasking kinase , 2003, Journal of Cell Science.

[28]  S. Goldhor.  Ecology , 1964, The Yale Journal of Biology and Medicine.

[29]  U. Schibler,et al.  CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP. , 2000, Genes & development.

[30]  Thomas K. Darlington,et al.  Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. , 1998, Science.

[31]  T. Monk,et al.  Circadian genes and bipolar disorder , 2005, Annals of medicine.