Dysregulation of Cytochrome P450 17α-Hydroxylase Messenger Ribonucleic Acid Stability in Theca Cells Isolated from Women with Polycystic Ovary Syndrome

Abstract

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 17α-hydroxylase (CYP17) [steroid 17α-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.