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Cryptochromes mediate rhythmic repression of the glucocorticoid receptor

JoeyXu 添加于 2011/12/21 13:20:05  1492次阅读 | 1次推荐 | 0个评论

Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors display interlinked diurnal cycling1, 2. However, mechanisms that logically explain the coordination of nuclear hormone receptors and the clock are poorly understood. Here we show that two circadian co-regulators, cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts: cryptochrome deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid receptor activation and promote repression. In mice, genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic–pituitary–adrenal axis coupled with increased glucocorticoid transactivation in the liver. Genomically, cryptochromes 1 and 2 associate with a glucocorticoid response element in the phosphoenolpyruvate carboxykinase 1 promoter in a hormone-dependent manner, and dexamethasone-induced transcription of the phosphoenolpyruvate carboxykinase 1 gene was strikingly increased in cryptochrome-deficient livers. These results reveal a specific mechanism through which cryptochromes couple the activity of clock and receptor target genes to complex genomic circuits underpinning normal metabolic homeostasis.

作 者:Katja A. Lamia,1, 2 Stephanie J. Papp,2 Ruth T. Yu,1 Grant D. Barish,1 N. Henriette Uhlenhaut,1, 3 Johan W. Jonker,1, 3 Michael Downes1 & Ronald M. Evans1
期刊名称: Nature
期卷页: 第卷 第期 ~页
学科领域:生命科学 » 生理学与整合生物学 » 系统生理学
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原文链接:http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10700.html
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相关报道: http://paper.sciencenet.cn/htmlpaper/201112211427678121299.shtm
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