Abramovitz Lilach, Shapira Tamar, Ben-Dror Iris, Dror Vardit, Granot Limor, Rousso Tal, Landoy Elad, Blau Lior, Thiel Gerald, Vardimon Lily
Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
Department of Medical Biochemistry and Molecular Biology, University of Saarland Medical Center, D-66421 Homburg, Germany.
J Biol Chem. 2008 Jan 4;283(1):110-119. doi: 10.1074/jbc.M707366200. Epub 2007 Nov 5.
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.
谷氨酰胺合成酶在神经系统中的限制主要是通过糖皮质激素受体和神经限制性沉默因子NRSF/REST的共同作用来实现的。糖皮质激素可诱导神经组织中谷氨酰胺合成酶的表达，而NRSF/REST则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端和C端包含两个独立的抑制结构域，且在非神经细胞中占主导性表达。然而，神经组织表达剪接变体REST4/5，其在分子的N端而非C端包含抑制结构域。在此我们表明，全长NRSF/REST或其C端结构域几乎可以完全抑制糖皮质激素对基因转录的诱导。相比之下，N端结构域不仅不能抑制激素反应，反而会显著刺激它。N端结构域的诱导活性由hBrm介导，hBrm仅在GR同时存在时被招募到启动子。重要的是，剪接变体REST4也具有类似的诱导活性。这些发现增加了NRSF/REST在谷氨酰胺合成酶调节中发挥双重作用的可能性。它在非神经细胞中抑制基因诱导，并通过其剪接变体在神经系统中增强激素反应。
