Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR7104, Inserm U964, Université de Strasbourg, Collège de France, Illkirch, 67404, France.
Cell. 2011 Apr 15;145(2):224-41. doi: 10.1016/j.cell.2011.03.027.
The glucocorticoid (GC) receptor (GR), when liganded to GC, activates transcription through direct binding to simple (+)GRE DNA binding sequences (DBS). GC-induced direct repression via GR binding to complex "negative" GREs (nGREs) has been reported. However, GR-mediated transrepression was generally ascribed to indirect "tethered" interaction with other DNA-bound factors. We report that GC-induces direct transrepression via the binding of GR to simple DBS (IR nGREs) unrelated to (+)GRE. These DBS act on agonist-liganded GR, promoting the assembly of cis-acting GR-SMRT/NCoR repressing complexes. IR nGREs are present in over 1000 mouse/human ortholog genes, which are repressed by GC in vivo. Thus variations in the levels of a single ligand can coordinately turn genes on or off depending in their response element DBS, allowing an additional level of regulation in GR signaling. This mechanism suits GR signaling remarkably well, given that adrenal secretion of GC fluctuates in a circadian and stress-related fashion.
糖皮质激素（GC）受体（GR）与 GC 结合后，通过直接结合简单的（+）GRE DNA 结合序列（DBS）激活转录。已经报道了 GC 通过与复杂的“负”GRE（nGRE）结合诱导直接抑制。然而，GR 介导的反式抑制通常归因于与其他结合 DNA 的因子的间接“系链”相互作用。我们报告说，GC 通过与与（+）GRE 无关的简单 DBS（IR nGREs）的 GR 结合诱导直接反式抑制。这些 DBS 作用于激动剂结合的 GR，促进顺式作用的 GR-SMRT/NCoR 抑制复合物的组装。IR nGRE 存在于超过 1000 个小鼠/人类同源基因中，这些基因在体内被 GC 抑制。因此，根据其反应元件 DBS，单一配体水平的变化可以协调地开启或关闭基因，从而在 GR 信号转导中增加了一个调节水平。鉴于肾上腺 GC 的分泌呈昼夜节律和应激相关的波动方式，这种机制非常适合 GR 信号转导。
