Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription.
Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription.
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DOI：
10.1038/ncb1922
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发表时间：
2009-09
影响因子：
21.3
通讯作者：
Hager GL
中科院分区：
文献类型：
--
作者：
Stavreva DA;Wiench M;John S;Conway-Campbell BL;McKenna MA;Pooley JR;Johnson TA;Voss TC;Lightman SL;Hager GL
对糖皮质激素受体（GR）作用的研究通常通过合成激素的长期刺激来评估基因反应。由于皮质类固醇以昼夜节律和高频（超昼夜）模式从肾上腺释放，因此此类治疗可能无法提供对生理激素作用的准确评估。在这里，我们表明，ultradian激素刺激诱导循环GR介导的转录调控，或基因脉冲，无论是在培养的细胞和动物模型。调节元件的平衡受体占据精确地跟踪配体脉冲。GR调控基因的新生RNA转录物以不同的量子形式释放，表明超日和恒定刺激诱导的转录程序之间存在深刻的差异。基因脉冲是由GR与反应元件的快速交换和通过伴侣机制的GR再循环驱动的，伴侣机制促进GR活化和响应于超日激素释放的再活化，从而将启动子活性与激素水平的自然发生的波动偶联。GR信号通路已被优化为对激素水平的波动做出迅速和及时的反应，这表明GR对基因靶点的生物学精确调节需要超日模式的激素刺激。
Studies on glucocorticoid receptor (GR) action typically assess gene responses by long-term stimulation with synthetic hormones. As corticosteroids are released from adrenal glands in a circadian and high-frequency (ultradian) mode, such treatments may not provide an accurate assessment of physiological hormone action. Here we demonstrate that ultradian hormone stimulation induces cyclic GR-mediated transcriptional regulation, or gene pulsing, both in cultured cells and in animal models. Equilibrium receptor-occupancy of regulatory elements precisely tracks the ligand pulses. Nascent RNA transcripts from GR-regulated genes are released in distinct quanta, demonstrating a profound difference between the transcriptional programs induced by ultradian and constant stimulation. Gene pulsing is driven by rapid GR exchange with response elements and by GR recycling through the chaperone machinery, which promotes GR activation and reactivation in response to the ultradian hormone release, thus coupling promoter activity to the naturally occurring fluctuations in hormone levels. The GR signalling pathway has been optimized for a prompt and timely response to fluctuations in hormone levels, indicating that biologically accurate regulation of gene targets by GR requires an ultradian mode of hormone stimulation.
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影响因子：
56.9
作者：
Karpova, Tatiana S.;Kim, Min J.;McNally, James G.
通讯作者：
McNally, James G.
影响因子：
56.9
作者：
BELCHETZ, PE;PLANT, TM;KNOBIL, E
通讯作者：
KNOBIL, E
影响因子：
4.8
作者：
Kramer, PR;Fragoso, G;Sinden, RR
通讯作者：
Sinden, RR
影响因子：
5.3
作者：
Klokk, Tove I.;Kurys, Piotr;Saatcioglu, Fahri
通讯作者：
Saatcioglu, Fahri
影响因子：
16
作者：
John, Sam;Sabo, Peter J.;Hager, Gordon L.
通讯作者：
Hager, Gordon L.