A silencer element in the first intron of the glutamine synthetase gene represses induction by glucocorticoids
A silencer element in the first intron of the glutamine synthetase gene represses induction by glucocorticoids
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DOI：
10.1210/me.2003-0062
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发表时间：
2004-01-01
影响因子：
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通讯作者：
Gebhardt, R
中科院分区：
文献类型：
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作者：
Gaunitz, F;Heise, K;Gebhardt, R
谷氨酰胺合成酶（GS）是最显著的糖皮质激素诱导的哺乳动物基因之一。在许多组织和细胞系中，单独使用合成糖皮质激素地塞米松可使GS的表达增加数倍。直接反应主要由细胞糖皮质激素受体介导，该受体与激素结合后，与基因的糖皮质激素应答元件（GREs）相互作用。在肝细胞源性细胞中，这种反应是由位于该基因第一个内含子中的GRE介导的。令人惊讶的是，尽管存在完整的糖皮质激素受体，肝细胞对GS表达增强的糖皮质激素没有反应，在相同的细胞中，糖皮质激素受体刺激其他基因的表达，如酪氨酸氨基转移酶。报告基因检测在GRE内含子下游发现了一个抑制糖皮质激素增强表达的序列元件。该消声器被命名为大鼠的GS消声器元件。凝胶迁移转移试验证明了肝细胞核提取物中一个因子的结合。这个未知因子被命名为GS沉默结合蛋白。在对糖皮质激素有反应并增强GS表达的FAO细胞中不存在GS，而在对糖皮质激素无反应的HepG2细胞中则存在。
The enzyme glutamine synthetase (GS) ranks as one of the most remarkable glucocorticoid-inducible mammalian genes. In many tissues and cell lines, the synthetic glucocorticoid dexamethasone alone increases GS expression several fold. The direct response is mainly mediated by a cellular glucocorticoid receptor that, upon binding of the hormone, interacts with glucocorticoid responsive elements (GREs) of the gene. In cells of hepatocellular origin the response is mediated by a GRE located in the first intron of the gene. Surprisingly, hepatocytes do not respond to glucocorticoids with enhanced GS expression, despite the presence of an intact glucocorticoid receptor, which, in the same cells, stimulates expression of other genes such as tyrosine amino transferase. Reporter gene assays identified a sequence element downstream from the intronic GRE that inhibits the enhancement of expression by glucocorticoids. This silencer was designated GS silencer element of the rat. Gel mobility shift assays demonstrate the binding of a factor in hepatocyte nuclear extract. This yet unknown factor was designated GS silencer-binding protein. It is absent in FAO cells that respond to glucocorticoids with enhanced expression of GS and present in HepG2 cells that do not respond.