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首页> 外文期刊>Molecular and Cellular Biology >DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita.
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DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita.

机译：DAX-1通过在肾上腺发育不全先天性缺失的羧基末端结构域抑制SF-1介导的反式激活。

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摘要

X-linked adrenal hypoplasia congenita (AHC) with hypogonadotropic hypogonadism was recently shown to be caused by mutations in a gene referred to as DAX-1, which encodes a novel member of the orphan nuclear receptor family. DAX-1 is homologous to other nuclear receptors in its carboxy-terminal region, but it lacks the characteristic zinc finger DNA-binding domain. The tissue distribution of DAX-1 (adrenal cortex, gonads, hypothalamus, and pituitary) is the same as that of another orphan nuclear receptor, steroidogenic factor 1 (SF-1), that is required for development of the adrenal glands and gonads. We examined whether DAX-1 and SF-1 might interact in the regulation of SF-1-responsive target genes. Coexpression of DAX-1 and SF-1 inhibited SF-1-mediated transactivation. DAX-1 was shown to interact directly with SF-1 in in vitro protein binding studies; however, it did not interfere with SF-1 binding to DNA in gel mobility shift assays. Transactivation by GAL4-SF-1 constructs was inhibited by DAX-1, indicating that neither the SF-1 DNA-binding domain nor the SF-1 binding sites are required for inhibition by DAX-1. A series of DAX-1 deletion mutants localized the inhibitory domain to the carboxy-terminal region of the protein. Deletion of this domain also reduced basal transcriptional silencing by GAL4-DAX-1. This inhibitory domain has been deleted in all naturally occurring AHC deletion mutants described to date. In addition, two naturally occurring point mutations in DAX-1 exhibited impaired inhibition of SF-1. We conclude that DAX-1 can inhibit SF-1 transcriptional activity and suggest that the loss of this inhibitory property in DAX-1 may account in part for the phenotype of AHC.
机译：最近发现具有性腺功能减退性腺功能减退的X连锁性肾上腺发育不全（AHC）是由称为DAX-1的基因中的突变引起的，该基因编码了孤儿核受体家族的一个新成员。 DAX-1在其羧基末端区域与其他核受体同源，但缺乏特征性的锌指DNA结合结构域。 DAX-1（肾上腺皮质，性腺，下丘脑和垂体）的组织分布与另一个孤儿核受体类固醇生成因子1（SF-1）的组织分布相同，这是肾上腺和性腺发育所必需的。我们检查了DAX-1和SF-1是否可能在SF-1反应性靶基因的调节中相互作用。 DAX-1和SF-1的共表达抑制SF-1介导的反式激活。在体外蛋白质结合研究中，DAX-1与SF-1直接相互作用。但是，它在凝胶迁移率迁移分析中不会干扰SF-1与DNA的结合。 GAL4-SF-1构建体的反式激活被DAX-1抑制，这表明SF-1 DNA结合域和SF-1结合位点都不是DAX-1抑制所必需的。一系列DAX-1缺失突变体将抑制域定位在蛋白质的羧基末端区域。该结构域的缺失还减少了GAL4-DAX-1的基础转录沉默。迄今为止，该抑制域已在所有天然存在的AHC缺失突变体中缺失。此外，DAX-1中两个自然发生的点突变表现出对SF-1的抑制作用减弱。我们得出的结论是DAX-1可以抑制SF-1转录活性，并暗示DAX-1中这种抑制特性的丧失可能部分解释了AHC的表型。

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