Dysregulation of cytochrome P450 17α-hydroxylase messenger ribonucleic acid stability in theca cells isolated from women with polycystic ovary syndrome
Dysregulation of cytochrome P450 17α-hydroxylase messenger ribonucleic acid stability in theca cells isolated from women with polycystic ovary syndrome
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DOI：
10.1210/jc.2004-1860
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发表时间：
2005-03-01
影响因子：
5.8
通讯作者：
McAllister, JM
中科院分区：
文献类型：
--
作者：
Wickenheisser, JK;Nelson-DeGrave, VL;McAllister, JM
多囊卵巢综合征(PCOS)是一种常见的以卵巢高雄激素血症为特征的生殖内分泌疾病。从多囊卵巢综合征患者卵巢分离的内膜细胞的特征是细胞色素P450 17-羟基酶(CYP17)[类固醇17-羟基酶/17，20裂解酶(P450c17)]的表达增加，这是一种类固醇生成酶，对雄激素的生物合成是必需的。编码P450c17(CYP17)的基因在PCOS囊膜中的表达增强，部分归因于正常细胞和PCOS细胞中CYP17启动子转录调控的差异。目前的研究检验了在长期培养的正常和PCOS卵泡膜细胞中，CYP17基因的表达是否也在mRNA稳定的水平上受到转录后调控。药物抑制转录半衰期测定结果表明，PCOS卵泡膜细胞的半衰期是正常卵泡膜细胞的2倍。Forsklin处理还延长了正常和PCOS卵泡膜细胞中CYP17mRNA的半衰期。体外信使核糖核酸降解研究表明，5‘-非翻译区增加了PCOS卵泡膜细胞中CYP17基因的稳定性，同时也证明了5’-非翻译区对细胞色素P450-17基因的稳定作用。这些研究表明，在PCOS卵泡膜细胞中，较慢的CYP17 mRNA衰变速度有助于增加稳定状态下的mRNA积累和增强CYP17基因的表达。
Polycystic ovary syndrome ( PCOS) is a common reproductive endocrine disorder characterized by ovarian hyperandrogenism. Theca interna cells isolated from the ovaries of women with PCOS are characterized by increased expression of cytochrome P450 17 alpha-hydroxylase (CYP17) [steroid 17 alpha-hydroxylase/ 17,20 lyase (P450c17)], a steroidogenic enzyme obligatory for the biosynthesis of androgens. Augmented expression of the gene encoding P450c17 ( CYP17) in PCOS theca has been attributed, in part, to differential transcriptional regulation of the CYP17 promoter in normal and PCOS cells. The present studies examine whether CYP17 gene expression is also posttranscriptionally regulated at the level of mRNA stability in normal and PCOS theca cells maintained in long-term culture. Determination of endogenous CYP17 mRNA half-life by pharmacological inhibition of transcription demonstrated that the half-life of CYP17 mRNA increased 2-fold in PCOS theca cells, compared with normal theca cells. Forskolin treatment also prolonged CYP17 mRNA half-life in both normal and PCOS theca cells. In vitro mRNA degradation studies demonstrated that the 5'-untranslated region confers increased stability to CYP17 mRNA in PCOS theca cells and showed that the 5'-untranslated region of CYP17 also confers forskolin-stimulated stabilization of CYP17 mRNA. These studies indicate that a slower rate of CYP17 mRNA decay contributes to increased steady-state mRNA accumulation and augmented CYP17 gene expression in PCOS theca cells.