Pearce D, Matsui W, Miner J N, Yamamoto K R
Department of Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
J Biol Chem. 1998 Nov 13;273(46):30081-5. doi: 10.1074/jbc.273.46.30081.
The glucocorticoid receptor (GR) displays distinct modes of regulation when bound at glucocorticoid response elements (GREs) bearing different binding sequences and arrangements of binding sites. For example, it has been shown to activate transcription synergistically with itself or with other regulatory factors, such as AP1, when bound to a consensus palindromic element or "simple GRE" that is multimerized or linked tightly with an AP1 site. In contrast, at certain "composite GREs" GR and AP1 bind to nonconsensus sequences, and GR either activates or represses depending on the subunit composition of AP1. To uncouple the contributions to regulatory behavior of binding sequences and binding element arrangements, we examined GR action at "paired elements," combinations of a simple GRE and a consensus AP1 site, separated by different distances. We found that GR synergized with either c-Jun or c-Jun-c-Fos at paired elements with GRE-AP1 site separations of >/=26 base pairs. In contrast, paired elements with separations of 14-18 base pairs mimicked the composite GRE, i.e. GR synergized with c-Jun and repressed c-Jun-c-Fos. In DNA binding studies, GR and AP1 cooccupied the paired elements. We conclude that the arrangement of binding sites within a compound response element can be a major determinant of regulatory factor action.
糖皮质激素受体（GR）与具有不同结合序列和结合位点排列的糖皮质激素反应元件（GRE）结合时，表现出不同的调节模式。例如，当与多聚化或与AP1位点紧密相连的共有回文元件或“简单GRE”结合时，已证明它能与自身或其他调节因子（如AP1）协同激活转录。相比之下，在某些“复合GRE”处，GR和AP1与非共有序列结合，GR根据AP1的亚基组成激活或抑制转录。为了区分结合序列和结合元件排列对调节行为的贡献，我们研究了GR在“配对元件”上的作用，即简单GRE和共有AP1位点的组合，它们被不同的距离隔开。我们发现，在GRE-AP1位点间距≥26个碱基对的配对元件上，GR与c-Jun或c-Jun-c-Fos协同作用。相比之下，间距为14-18个碱基对的配对元件模拟了复合GRE，即GR与c-Jun协同作用并抑制c-Jun-c-Fos。在DNA结合研究中，GR和AP1共同占据配对元件。我们得出结论，复合反应元件内结合位点的排列可能是调节因子作用的主要决定因素。
