期刊
SCIENCE
卷 311, 期 5763, 页码 1002-1005出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1121613
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资金
- NIDDK NIH HHS [DK 19525, DK45586] Funding Source: Medline
- NIMH NIH HHS [R01 MH058324, R01 MH058324-07, R01 MH058324-08, MH058324] Funding Source: Medline
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 GSK3 beta 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.
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