Expression profiles of SF-1, DAX1, and CYP17 in the human fetal adrenal gland: Potential interactions in gene regulation
Expression profiles of SF-1, DAX1, and CYP17 in the human fetal adrenal gland: Potential interactions in gene regulation
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DOI：
10.1210/me.15.1.57
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发表时间：
2001-01-01
影响因子：
--
通讯作者：
Parker, KL
中科院分区：
文献类型：
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作者：
Hanley, NA;Rainey, WE;Parker, KL
细胞色素P450 17 α-羟化酶/17-20裂解酶（P450（C17））是甾体激素生物合成的关键分支酶。在人类妊娠期间，P450（C17）是胎儿肾上腺皮质产生硫酸脱氢表雄烯二酮和睾丸产生介导男性性分化的雄激素所必需的。在这项研究中，我们研究了两个孤儿核受体，类固醇生成因子1（SF-1）和DAX 1的人类CYP 17基因的调节。在人类胚胎中，SF-1和DAX 1从受孕后33天（dpc）开始就在整个发育中的肾上腺皮质中表达。相反，P450（C17）的表达，开始之间的41和44 dpc，是有限的胎儿区。人CYP 17基因的5 '侧翼区含有三个功能性SF-1元件，它们共同介导SF-1对启动子活性的大于或等于25倍的诱导。在含有所有三种功能性SF-1元件的构建体中，DAX 1抑制这种激活大于或等于55%。在仅存在一个或两个SF-1元件的情况下，即使SF-1反式激活持续，DAX 1抑制也丧失。这些数据表明，DAX 1对SF-1介导的人CYP 17基因激活的有效抑制需要多种SF-1元件。SF-1和DAX 1的相反作用可以微调不同内分泌组织中各种SF-1靶基因的差异反应。
Cytochrome P450 17 alpha -hydroxylase/17-20 lyase (P450(C17)) is a critical branchpoint enzyme for steroid hormone biosynthesis. During human gestation, P450(C17) is required for the production of dehydroepiandrostenedione sulfate by the fetal adrenal cortex and for testicular production of androgens that mediate male sexual differentiation. In this study, we investigate the regulation of the human CYP17 gene by two orphan nuclear receptors, steroidogenic factor 1 (SF-1) and DAX1. In human embryos, SF-1 and DAX1 are expressed throughout the developing adrenal cortex from its inception at 33 days post conception (dpc). In contrast, P450(C17) expression, which commences between 41 and 44 dpc, is limited to the fetal zone. The 5'-flanking region of the human CYP17 gene contains three functional SF-1 elements that collectively mediate a greater than or equal to 25-fold induction of promoter activity by SF-1. In constructs containing all three functional SF-1 elements, DAX1 inhibited this activation by greater than or equal to 55%. In the presence of only one or two SF-1 elements, DAX1 inhibition was lost even though SF-1 transactivation persisted. These data suggest that efficient repression of SF-1-mediated activation of the human CYP17 gene by DAX1 requires multiple SF-1 elements. Opposing effects of SF-1 and DAX1 may fine tune the differential responses of various SF-1 target genes in different endocrine tissues.