Xu Bin, Yang Wei-Hsiung, Gerin Isabelle, Hu Chang-Deng, Hammer Gary D, Koenig Ronald J
Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan 48109-5678, USA.
Mol Cell Biol. 2009 Apr;29(7):1719-34. doi: 10.1128/MCB.01010-08. Epub 2009 Feb 2.
The nuclear receptor steroidogenic factor 1 (SF-1) is essential for adrenal development and steroidogenesis. The atypical orphan nuclear receptor Dax-1 binds to SF-1 and represses SF-1 target genes. Paradoxically, however, loss-of-function mutations of Dax-1 also cause adrenal hypoplasia, suggesting that Dax-1 may function as an SF-1 coactivator under some circumstances. Indeed, we found that Dax-1 can function as a dosage-dependent SF-1 coactivator. Both SF-1 and Dax-1 bind to steroid receptor RNA activator (SRA), a coactivator that functions as an RNA. The coactivator TIF2 also associates with Dax-1 and synergistically coactivates SF-1 target gene transcription. A naturally occurring Dax-1 mutation inhibits this transactivation, and the mutant Dax-1-TIF2 complex mislocalizes in living cells. Coactivation by Dax-1 is abolished by SRA knockdown. The expression of the steroidogenic gene products steroidogenic acute regulatory protein (StAR) and melanocortin 2 receptor is reduced in adrenal Y1 cells following the knockdown of endogenous SRA. Similarly, the knockdown of endogenous Dax-1 downregulates the expression of the steroidogenic gene products CYP11A1 and StAR in both H295R adrenal and MA-10 Leydig cells. These findings reveal novel functions of SRA and Dax-1 in steroidogenesis and adrenal biology.
核受体类固醇生成因子1（SF-1）对于肾上腺发育和类固醇生成至关重要。非典型孤儿核受体Dax-1与SF-1结合并抑制SF-1靶基因。然而，矛盾的是，Dax-1的功能丧失突变也会导致肾上腺发育不全，这表明Dax-1在某些情况下可能作为SF-1的共激活因子发挥作用。事实上，我们发现Dax-1可以作为剂量依赖性的SF-1共激活因子发挥作用。SF-1和Dax-1都与类固醇受体RNA激活剂（SRA）结合，SRA是一种作为RNA发挥作用的共激活因子。共激活因子TIF2也与Dax-1相关联，并协同共激活SF-1靶基因转录。一种天然存在的Dax-1突变会抑制这种反式激活，并且突变的Dax-1-TIF2复合物在活细胞中定位错误。SRA敲低会消除Dax-1的共激活作用。在内源性SRA敲低后，肾上腺Y1细胞中类固醇生成基因产物类固醇生成急性调节蛋白（StAR）和黑皮质素2受体的表达降低。同样，内源性Dax-1的敲低会下调H295R肾上腺细胞和MA-10睾丸间质细胞中类固醇生成基因产物CYP11A1和StAR的表达。这些发现揭示了SRA和Dax-1在类固醇生成和肾上腺生物学中的新功能。
