Dual role of NRSF/REST in activation and repression of the glucocorticoid response
Dual role of NRSF/REST in activation and repression of the glucocorticoid response
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DOI：
10.1074/jbc.m707366200
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发表时间：
2008-01-04
影响因子：
4.8
通讯作者：
Vardimon, Lily
中科院分区：
文献类型：
--
作者：
Abramovitz, Lilach;Shapira, Tamar;Vardimon, Lily
谷氨酰胺合成酶对神经系统的限制作用主要通过糖皮质激素受体和神经限制性沉默因子NRSF/REST的相互作用来实现。糖皮质激素诱导神经组织中谷氨酰胺合成酶的表达，而NRSF/REST抑制非神经细胞中的激素反应。NRSF/REST是一种模块化蛋白，在分子的N和C末端含有两个独立的阻遏结构域，并且主要在非神经细胞中表达。然而，神经组织表达剪接变体REST 4/5，其在分子的N端而不是C端含有阻遏结构域。在这里，我们表明，全长NRSF/REST或其C-末端结构域可以抑制几乎完全诱导基因转录糖皮质激素。相比之下，N-末端结构域不仅不能抑制激素反应，反而显著刺激激素反应。N-末端结构域的诱导活性由hBrm介导，hBrm仅在GR的伴随存在下被募集到启动子。重要的是，剪接变体REST 4也发挥类似的诱导活性。这些发现提出了NRSF/REST在调节谷氨酰胺合成酶方面发挥双重作用的可能性。它抑制非神经细胞中的基因诱导，并通过其剪接变体增强神经系统中的激素反应。
Restriction of glutamine synthetase to the nervous system is mainly achieved through the mutual function of the glucocorticoid receptor and the neural restrictive silencing factor, NRSF/REST. Glucocorticoids induce glutamine synthetase expression in neural tissues while NRSF/REST represses the hormonal response in non-neural cells. NRSF/REST is a modular protein that contains two independent repression domains, at the N and C termini of the molecule, and is dominantly expressed in nonneural cells. Neural tissues express however splice variants, REST4/5, which contain the repression domain at the N, but not at the C terminus of the molecule. Here we show that full-length NRSF/REST or its C-terminal domain can inhibit almost completely the induction of gene transcription by glucocorticoids. By contrast, the N-terminal domain not only fails to repress the hormonal response but rather stimulates it markedly. The inductive activity of the N-terminal domain is mediated by hBrm, which is recruited to the promoter only in the concomitant presence of GR. Importantly, a similar inductive activity is also exerted by the splice variant REST4. These findings raise the possibility that NRSF/REST exhibits a dual role in regulation of glutamine synthetase. It represses gene induction in nonneural cells and enhances the hormonal response, via its splice variant, in the nervous system.