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A functional genomics strategy reveals Rora as a component of the mammalian circadian clock 总被引:21,自引:0,他引:21
Sato TK Panda S Miraglia LJ Reyes TM Rudic RD McNamara P Naik KA FitzGerald GA Kay SA Hogenesch JB 《Neuron》2004,43(4):527-537
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Plasminogen activator inhibitor type 1 (PAI-1) is a major physiologic regulator of the fibrinolytic system and has recently gained recognition as a modulator of inflammation and atherosclerosis. PAI-1 exhibits circadian rhythmicity in its expression, peaking in the early morning, which is associated with increased risk for cardiovascular events. However, the mechanisms that determine PAI-1 circadian rhythmicity remain poorly understood. We discovered that the orphan nuclear receptor Rev-erb alpha, a core component of the circadian loop, represses human PAI-1 gene expression through two Rev-erb alpha binding sites in the PAI-1 promoter. Mutations of these sites, as well as RNA interference targeting endogenous Rev-erb alpha and its corepressors, led to increased expression of the PAI-1 gene. Furthermore, glycogen synthase kinase 3beta (GSK3beta) contributes to pai-1 repression by phosphorylating and stabilizing Rev-erb alpha protein, which can be blocked by lithium. Interestingly, serum shock generated circadian oscillations in PAI-1 mRNA in NIH3T3 cells, suggesting that PAI-1 is a direct output gene of the circadian loop. Ectopic expression of a stabilized form of Rev-erb alpha that mimics GSK3beta phosphorylation dramatically dampened PAI-1 circadian oscillations. Thus, our results suggest that Rev-erb alpha is a major determinant of the circadian PAI-1 expression and a potential modulator of the morning susceptibility to myocardial infarction. 相似文献
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