Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.
Cryptochromes mediate rhythmic repression of the glucocorticoid receptor.
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DOI：
10.1038/nature10700
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发表时间：
2011-12-14
期刊：
影响因子：
64.8
通讯作者：
Evans, Ronald M.
中科院分区：
文献类型：
--
作者：
Lamia, Katja A.;Papp, Stephanie J.;Yu, Ruth T.;Barish, Grant D.;Uhlenhaut, N. Henriette;Jonker, Johan W.;Downes, Michael;Evans, Ronald M.
哺乳动物的代谢是高度昼夜节律和主要的激素回路，涉及核激素受体（NR）显示相互关联的昼夜循环。然而，逻辑上解释NR和时钟协调的机制却知之甚少。在这里，我们表明，两种昼夜节律协同调节因子，隐花色素1（Cry 1）和2（Cry 2），以配体依赖性方式与糖皮质激素受体（GR）相互作用，并在小鼠胚胎成纤维细胞（MEF）中全面改变对糖皮质激素的转录反应：Cry缺陷极大地减少了基因抑制，并使地塞米松（Dex）的数量增加了一倍诱导的基因表明隐花色素广泛地对抗GR激活并促进抑制。在小鼠中，Cry 1和/或Cry 2的遗传缺失导致葡萄糖耐受不良和组成性高水平的循环皮质酮，这表明下丘脑-垂体-肾上腺（HPA）轴的抑制减少，加上肝脏中糖皮质激素反式激活增加。在基因组学上，Cry 1和Cry 2与磷酸烯醇丙酮酸羧激酶1（Pck 1）启动子中的糖皮质激素反应元件（GRE）以依赖于葡萄糖的方式相关联，并且Dex诱导的pck 1转录在Cry缺陷的肝脏中显著增加。这些结果揭示了一种特定的机制，通过这种机制，隐花色素将时钟和受体靶基因的活性偶联到支持正常代谢稳态的复杂基因组回路。
Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors (NRs) display interlinked diurnal cycling. However, mechanisms that logically explain the coordination of NRs and the clock are poorly understood. Here we show that two circadian co-regulators, cryptochromes 1 (Cry1) and 2 (Cry2), interact with the glucocorticoid receptor (GR) in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts (MEFs): Cry deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone (Dex) induced genes suggesting that cryptochromes broadly oppose GR activation and promote repression. In mice, genetic loss of Cry1 and/or Cry2 resulted in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal (HPA) axis coupled with increased glucocorticoid transactivation in the liver. Genomically, Cry1 and Cry2 associate with a glucocorticoid response element (GRE) in the phosphoenolpyruvate carboxykinase 1 (Pck1) promoter in a hormone-dependent manner, and Dex-induced transcription of pck1 was strikingly increased in Cry-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.
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DOI：
10.1073/pnas.0909733106
发表时间：
2009-10-13
影响因子：
11.1
作者：
So, Alex Y. -L.;Bernal, Teresita U.;Feldman, Brian J.
通讯作者：
Feldman, Brian J.
影响因子：
10.5
作者：
Stratmann, Markus;Stadler, Frederic;Ripperger, Juergen A.
通讯作者：
Ripperger, Juergen A.
影响因子：
64.5
作者：
Yang, Xiaoyong;Downes, Michael;Evans, Ronald M.
通讯作者：
Evans, Ronald M.
影响因子：
56.9
作者：
Balsalobre, A;Brown, SA;Schibler, U
通讯作者：
Schibler, U
影响因子：
56.9
作者：
WEINBERGER, C;HOLLENBERG, SM;EVANS, RM
通讯作者：
EVANS, RM