Nuclear receptor Rev-erbalpha 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 GSK3beta phosphorylates and stabilizes the orphan nuclear receptor Rev-erbalpha, a negative component of the circadian clock. Lithium treatment of cells leads to rapid proteasomal degradation of Rev-erbalpha and activation of clock gene Bmal1. A form of Rev-erbalpha that is insensitive to lithium interferes with the expression of circadian genes. Control of Rev-erbalpha protein stability is thus a critical component of the peripheral clock and a biological target of lithium therapy.
Division of Endocrinology, Diabetes, and Metabolism, and University of Pennsylvania School of Medicine, 415 Curie Boulevard, Philadelphia, PA 19104, USA.
Lei
L
Yin
Jing
J
Wang
Peter S
PS
Klein
Mitchell A
MA
Lazar
D056930:ARNTL Transcription Factors; D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001683:Biological Clocks / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002940:Circadian Rhythm / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D056930:ARNTL Transcription Factors; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; C538960:BMAL1 protein, human; C538961:Bmal1 protein, mouse; C064353:NR1D1 protein, human; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse