Selective DNA binding by the androgen receptor as a mechanism for hormone-specific gene regulation
Selective DNA binding by the androgen receptor as a mechanism for hormone-specific gene regulation
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DOI：
10.1016/s0960-0760(00)00154-0
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发表时间：
2001-01-01
影响因子：
4.1
通讯作者：
Rombauts, W
中科院分区：
文献类型：
--
作者：
Claessens, F;Verrijdt, G;Rombauts, W
类固醇激素通过激活作为转录因子的特定受体来控制许多生理过程。在体内，这些受体中的每一个都有一组特定的靶基因，但在体外，糖皮质激素、孕激素、盐皮质激素和雄激素受体(I类受体)都能识别反应元件，这些反应元件是由带有三个核苷酸间隔区的5‘-TGTTCT-3’类似序列的反向重复组成的。这就提出了一个问题，不同类固醇反应的体内特异性是如何调节的。为了揭示其中的机制，我们比较了前盆、分泌成分和性别限制蛋白基因的雄激素选择性增强子与小鼠乳腺肿瘤病毒启动子和C3(1)基因中的非选择性增强子的结构特征。前盆启动子包含一个雄激素反应元件，该元件可被雄激素受体高度亲和力识别，但不能被其他I类受体识别。雄激素和糖皮质激素受体的DNA结合域之间的交换实验表明，导致这种特异性的不是第一个锌指，而是第二个锌指和部分铰链区。三种AR专一性氨基酸均参与前盆Are识别，但不参与C3(1)均受AR结合。这些残基的位置强烈表明，前盆地中参与了另一种二聚界面的结合。随后，我们可以在凝胶滞留实验和转染实验中证明AR与5‘-TGTTCT-3’类似序列的直接重复序列结合。此外，雄激素特异性增强子都包含直接重复，点突变会将这些元件的性质改变为反向重复，从而导致特异性的改变。因此，直接重复元件似乎可以是AR特异性的决定因素，了解这些DNA元件如何影响受体二聚体的特性将是令人兴奋的，涉及配体结合、氨基末端结构域和配体结合结构域之间的相互作用、共激活子的招募以及与其他转录因子的协同作用。(C)2001爱思唯尔科学有限公司。保留所有权利。
Steroid hormones control many physiological processes by activating specific receptors that act as transcription factors. In vivo, each of these receptors has a specific set of target genes, but in vitro the glucocorticoid, progesterone, mineralocorticoid and androgen receptors (class I receptors) all recognise response elements which are organised as inverted repeats of 5'-TGTTCT-3'-like sequences with a three nucleotide spacer. This poses the question how the in vivo specificity of the different steroid responses is mediated. To unravel the mechanisms involved, we have compared the structural features of the androgen-selective enhancers of the probasin, the secretory component and the sex-limited protein genes with those of non-selective enhancers in the mouse mammary tumour viral promoter and the C3(1) gene. The probasin promoter contains an androgen response element which is recognised with high affinity by the androgen receptor, but not by the other class I receptors. Swapping experiments between the DNA-binding domains of the androgen and glucocorticoid receptor revealed that it is not the first zinc finger, but rather the second zinc finger and part of the hinge region which contribute to this specificity. Three AR-specific aminoacids are involved in the probasin ARE recognition, but not in the C3(1) ARE binding by the AR. The location of these residues strongly suggests that an alternative dimerisation interface is involved in the probasin ARE binding. We could subsequently demonstrate that the AR binds direct repeats of 5'-TGTTCT-3'-like sequences in gel retardation assays as well as in transfection experiments. Moreover, the androgen-specific enhancers all contain direct repeats, and point mutations that change the nature of these elements into inverted repeats result in a change of specificity. It seems, therefore, that direct repeat elements can be the determinants of the AR-specificity, It will be exciting to learn how such DNA elements will affect the properties of the receptor dimer with respect to ligand binding, interactions between the aminoterminal domain and the ligand-binding domain, the recruitment of co-activators and cooperativity with other transcription factors. (C) 2001 Elsevier Science Ltd. All rights reserved.