Selective recruitment of p160 coactivators on glucocorticoid-regulated promoters in Schwann cells
Selective recruitment of p160 coactivators on glucocorticoid-regulated promoters in Schwann cells
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DOI：
10.1210/me.2004-0241
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发表时间：
2004-12-01
影响因子：
--
通讯作者：
Massaad, C
中科院分区：
文献类型：
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作者：
Grenier, J;Trousson, A;Massaad, C
在神经系统中，糖皮质激素在发育和整个生命过程中发挥着重要作用。我们研究了糖皮质激素受体（GR）的作用机制及其与p160辅激活因子家族成员[类固醇受体辅激活因子（SRC）-1（a和e），SRC-2和SRC-3]在小鼠雪旺细胞（MSC 80）中的相互作用。我们发现三种p160在MSC 80细胞中均有表达。我们已经通过功能性过表达和RNA干扰实验表明，GR对这些共激活因子的募集是依赖于启动子的。含有两个糖皮质激素反应元件（GRE）2-TATA的最小启动子募集SRC-1（a和e）和SRC-3，而SRC-2被排除在外。在更复杂的小鼠乳腺肿瘤病毒启动子的背景下，GR招募SRC-1 e和SRC-2，而SRC-1a和SRC-3不受影响。此外，我们已经确定了细胞溶质天冬氨酸氨基转移酶作为GR的靶基因在MSC 80细胞的微阵列实验。GR在细胞溶质天冬氨酸转氨酶启动子的背景下专门招募SRC-1 e。由于SRC-1是无处不在的GR的共激活因子，我们进一步研究了GR和这种共激活因子之间的相互作用，在雪旺细胞的报告分析和免疫细胞化学实验与SRC-1的删除形式。我们已经发现SRC-1通过其两个核受体结合结构域与GR意外地相互作用，从而提供了神经系统内GR信号传导的新机制。
In the nervous system, glucocorticoid hormones play a major role during development and throughout life. We studied the mechanisms of action of the glucocorticoid receptor (GR) and its interactions with p160 coactivator family members [ steroid receptor coactivator (SRC)-1 (a and e), SRC-2 and SRC-3] in mouse Schwann cells (MSC80). We found that the three p160s were expressed in MSC80 cells. We have shown by functional overexpression and RNA interference experiments that the recruitment of these coactivators by the GR is promoter dependent. A minimal promoter containing two glucocorticoid response elements, (GRE)2-TATA, recruits SRC-1 (a and e) and SRC-3, whereas SRC-2 is excluded. Within the context of the more complex mouse mammary tumor virus promoter, GR recruits SRC-1e and SRC-2, whereas SRC-1a and SRC-3 are not implicated. Furthermore, we have identified cytosolic aspartate aminotransferase as a GR target gene in MSC80 cells by microarray experiments. The GR recruits exclusively SRC-1e in the context of the cytosolic aspartate aminotransferase promoter. Because SRC-1 is the omnipresent coactivator of GR, we further investigated the interactions between GR and this coactivator in Schwann cells by reporter assays and immunocytochemistry experiments with deleted forms of SRC-1. We have shown that SRC-1 unexpectedly interacts with GR via its two nuclear receptor binding domains, thus providing a novel mechanism of GR signaling within the nervous system.