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Cryptochromes mediate rhythmic repression of the glucocorticoid receptor

机译:隐色染料介导糖皮质激素受体的节律性抑制

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摘要

Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors display interlinked diurnal cycling. 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.
机译:哺乳动物的代谢是高度昼夜节律的,涉及核激素受体的主要激素循环表现出相互联系的昼夜循环。但是,对逻辑上解释核激素受体和时钟协调作用的机制了解甚少。在这里,我们显示了两个昼夜节律共同调节剂,隐色染料1和2与糖皮质激素受体以配体依赖的方式相互作用,并全局改变了小鼠胚胎成纤维细胞中对糖皮质激素的转录反应:隐色染料的缺乏极大地降低了基因阻遏作用,并使数目大约增加了一倍地塞米松诱导的基因的研究表明,隐色染料广泛地反对糖皮质激素受体的激活并促进抑制。在小鼠中,隐色素1和/或2的遗传损失会导致葡萄糖耐受不良和循环皮质酮的组成型高水平表达,提示对下丘脑-垂体-肾上腺轴的抑制作用降低,同时肝脏中糖皮质激素的反式激活增加。基因组学上,隐色染料1和2在激素依赖性的方式与磷酸烯醇丙酮酸羧激酶1启动子中的糖皮质激素反应元件相关联,地塞米松诱导的磷酸烯醇丙酮酸羧激酶1基因的转录在隐铬缺乏的肝脏中显着增加。这些结果揭示了一种特殊的机制,通过这种机制,隐色染料将时钟和受体靶基因的活性与支撑正常代谢稳态的复杂基因组回路相结合。

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  • 来源
    《Nature》 |2011年第7378期|p.552-556|共5页
  • 作者单位

    Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.,Departmentof Chemical Physiology, The Scripps Research Institute,10550 North Torrey Pines Road, La Jolla, California 92037, USA.;

    Departmentof Chemical Physiology, The Scripps Research Institute,10550 North Torrey Pines Road, La Jolla, California 92037, USA.;

    Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.;

    Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.;

    Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.,Max-Delbrueck-Centrum Fuer Molekulare Medizin, Genetics and Physiology, Berlin, 13125, Germany;

    Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.,Center for Liver, Digestive and Metabolic Diseases, University Medical Center Groningen, The Netherlands;

    Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.;

    Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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