Lalli E, Bardoni B, Zazopoulos E, Wurtz J M, Strom T M, Moras D, Sassone-Corsi P
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch-Strasbourg, France.
Mol Endocrinol. 1997 Dec;11(13):1950-60. doi: 10.1210/mend.11.13.0038.
The DAX-1 gene encodes an unusual member of the nuclear hormone receptor superfamily. Mutations in the human DAX-1 gene cause X-linked adrenal hypoplasia congenita associated with hypogonadotropic hypogonadism. We have shown that DAX-1 binds to hairpin secondary structures and blocks steroidogenesis in adrenal cells via transcriptional repression of the steroidogenic acute regulatory protein (StAR) promoter. Here we have investigated the molecular mechanism of DAX-1-mediated repression. We show that the DAX-1 C terminus contains a potent transcriptional silencing activity, which can be transferred to a heterologous DNA-binding domain. Deletion analysis and modeling of DAX-1 structure identify two cooperating domains required for the silencing function, one located within helix H3 and the other within H12. The silencing function is cell- and promoter-specific. Strikingly, two point mutations (R267P and deltaV269) found in adrenal hypoplasia patients impair silencing. These findings suggest that transcriptional silencing by DAX-1 plays a critical role in the pathogenesis of adrenal hypoplasia congenita.
DAX-1基因编码核激素受体超家族中一个不同寻常的成员。人类DAX-1基因的突变会导致与促性腺激素分泌不足性性腺功能减退相关的X连锁先天性肾上腺发育不全。我们已经表明，DAX-1与发夹二级结构结合，并通过对类固醇生成急性调节蛋白（StAR）启动子的转录抑制来阻断肾上腺细胞中的类固醇生成。在此，我们研究了DAX-1介导的抑制的分子机制。我们发现DAX-1的C末端包含一种强大的转录沉默活性，这种活性可以转移到异源DNA结合结构域。对DAX-1结构的缺失分析和建模确定了沉默功能所需的两个协同结构域，一个位于H3螺旋内，另一个位于H12螺旋内。沉默功能具有细胞和启动子特异性。引人注目的是，在肾上腺发育不全患者中发现的两个点突变（R267P和deltaV269）损害了沉默作用。这些发现表明，DAX-1介导的转录沉默在先天性肾上腺发育不全的发病机制中起关键作用。
