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This version published online on December 14, 2004
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1860
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Submitted on September 20, 2004
Accepted on December 3, 2004

Dysregulation of Cytochrome P450 17{alpha}-Hydroxylase Messenger RNA Stability in Theca Cells Isolated from Women with Polycystic Ovary Syndrome (PCOS)

Jessica K. Wickenheisser, Velen L. Nelson-DeGrave, and Jan M. McAllister*

Departments of Cellular and Molecular Physiology (J.K.W., V.L.N-D., J.M.M.) and Obstetrics and Gynecology (J.M.M.), The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033

* To whom correspondence should be addressed. E-mail: jmcallister{at}psu.edu.

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 (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 post-transcriptionally 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 (UTR) confers increased stability to CYP17 mRNA in PCOS theca cells, and showed that the 5'-UTR 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.
Key words: Theca • polycystic ovary syndrome • CYP17 • mRNA stability




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