ESTRADIOL INDUCTION OF A GLUCOCORTICOID-RESPONSIVE GENE BY A CHIMERIC RECEPTOR
ESTRADIOL INDUCTION OF A GLUCOCORTICOID-RESPONSIVE GENE BY A CHIMERIC RECEPTOR
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DOI：
10.1038/325075a0
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发表时间：
1987-01-01
期刊：
影响因子：
64.8
通讯作者：
CHAMBON, P
中科院分区：
文献类型：
--
作者：
GREEN, S;CHAMBON, P
类固醇激素受体是一类细胞特异性的反式作用转录调节因子，其活性受激素特异性结合的控制。受体复合物似乎与特定靶基因的启动子/增强子元件结合，导致转录激活（综述见参考文献1和2）。雌激素受体3，4，糖皮质激素受体5，6和孕酮受体之间的序列比较（参考文献7，8和未发表的结果）和定点突变分析9 -11，已经在每种受体中鉴定出至少两个对类固醇受体功能重要的功能域。区域E（图1a）是酶结合结构域9;区域C是66个氨基酸的区域（图1a，B），其比酶结合结构域更高度保守，并且具有形成至少两个锌稳定的“DNA结合指”的潜力，类似于为异种转录因子TFIIIA提出的那些7，12，13。我们3，4和其他人14认为，这一区域可能是受体的DNA结合域。我们在这里表明，点突变取代两个半胱氨酸的两个组氨酸在第一个潜在的DNA结合指的人雌激素受体（hER）阻止它激活基因转录。我们进一步表明，嵌合受体形成的HER与人糖皮质激素受体（hGR）的66个氨基酸的区域替换激活糖皮质激素诱导基因的表达，但不是雌激素诱导基因，在雌二醇的存在下。因此，C区决定受体对靶基因的特异性。
Steroid hormone receptors are a class of cell-specifictrans-acting transcription regulatory factors whose activity is controlled by specific binding of the hormone. The hormone-receptor complex appears to associate with promoter/enhancer elements of specific target genes, resulting in activation of transcription (see refs 1 and 2 for reviews). Sequence comparison between the oestrogen3,4, glucocorticoid5,6and progesterone receptors (refs 7,8 and unpublished results) and site-directed mutation analysis9–11, has identified in each at least two functional domains important for steroid receptor function. Region E (Fig. la), is the hormone-binding domain9; region C is a 66-amino-acid region (Figs la,b) that is more highly conserved than the hormone-binding domain and has the potential to form at least two zinc-stabilized 'DNA-binding fingers' analogous to those proposed for theXenopustranscription factor TFIIIA7,12,13. We3,4and others14have suggested that this region may be the receptor's DNA-binding domain. We show here that point mutations replacing two cysteines by two histidines in the first potential DNA-binding finger of the human oestrogen receptor (hER) prevent it from activating gene transcription. We further show that a chimaeric receptor formed by replacing this 66-amino-acid region of the HER with that of the human glucocorticoid receptor (hGR) activates expression of a glucocorticoid-inducible gene, but not of an oestrogen-inducible gene, in the presence of oestradiol. Thus, region C determines the receptor's specificity for target genes.