Lalli E, Melner M H, Stocco D M, Sassone-Corsi P
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université Louis Pasteur, Strasbourg, France.
Endocrinology. 1998 Oct;139(10):4237-43. doi: 10.1210/endo.139.10.6217.
DAX-1 is an unusual member of the nuclear hormone receptor superfamily whose expression is mainly, but not uniquely, restricted to steroidogenic tissues. We have recently shown that DAX-1 can block the first and rate-limiting step in steroid biosynthesis by repressing StAR (steroidogenic acute regulatory protein) expression. Here we show that DAX-1 blocks steroid production at multiple levels in the Y-1 mouse adrenocortical tumor cell line. Expression of DAX-1 in Y-1 cells significantly impairs both basal and cAMP-stimulated steroid production, without affecting the functionality of the cAMP-responsive PKA pathway. Experiments using an hydroxylated cholesterol derivative show that biochemical steps in steroidogenesis subsequent to cholesterol delivery to mitochondria are also impaired in Y-1 cells expressing DAX-1. This is explained by the repression of P450scc and 3beta-HSD expression, in addition to StAR. DAX-1 expression in Y-1 cells results in the inhibition of the activity of the StAR, P450scc and 3beta-HSD promoters. An inappropriate steroidogenic block in the male fetus might have an important role in the pathogenesis of sex reversal syndromes caused by a duplication of the genomic region of the X chromosome containing the DAX-1 gene.
DAX-1是核激素受体超家族中一个不同寻常的成员，其表达主要（但并非唯一）局限于类固醇生成组织。我们最近发现，DAX-1可通过抑制类固醇生成急性调节蛋白（StAR）的表达来阻断类固醇生物合成的第一步及限速步骤。在此我们表明，DAX-1在Y-1小鼠肾上腺皮质肿瘤细胞系中可在多个水平阻断类固醇生成。DAX-1在Y-1细胞中的表达显著损害基础及cAMP刺激的类固醇生成，但不影响cAMP反应性蛋白激酶A（PKA）途径的功能。使用羟基化胆固醇衍生物进行的实验表明，在将胆固醇转运至线粒体之后的类固醇生成生化步骤在表达DAX-1的Y-1细胞中也受到损害。除了StAR之外，这可通过P450scc和3β-羟基类固醇脱氢酶（3β-HSD）表达受到抑制来解释。DAX-1在Y-1细胞中的表达导致StAR、P450scc和3β-HSD启动子活性受到抑制。男性胎儿中不适当的类固醇生成阻滞可能在由包含DAX-1基因的X染色体基因组区域重复导致的性反转综合征发病机制中起重要作用。
