Aromatase promoter I.f is regulated by progesterone receptor in mouse hypothalamic neuronal cell lines

M. Bertan Yilmaz, Andrew Wolfe, Hong Zhao, David C. Brooks, Serdar E. Bulun

Research output: Contribution to journalArticlepeer-review

Abstract

Aromatase catalyzes the conversion of C19 steroids to estrogens. Aromatase and progesterone, both of which function at different steps of steroidogenesis, are crucial for the sexually dimorphic development of the fetal brain and the regulation of gonadotropin secretion and sexual interest in adults. The aromatase gene (Cyp19a1) is selectively expressed in distinct neurons of the mouse hypothalamus through a distal brain-specific promoter, I.f, located ~40 kb upstream of the coding region. However, the regulation of aromatase expression in the brain is not well understood. In this study, we investigated a short feedback effect of progesterone analogues on aromatase mRNA expression and enzyme activity in estrogen receptor α (Esr1)-positive or -negative mouse embryonic hypothalamic neuronal cell lines that express aromatase via promoter I.f. In a hypothalamic neuronal cell line that highly expresses aromatase, progesterone receptor (Pgr), and Esr1, a progesterone agonist, R5020, inhibited aromatase mRNA level and enzyme activity. The inhibitory effect of R5020 was reversed by its antagonist, RU486. Deletion mutants of promoter I.f suggested that inhibition of aromatase expression by progesterone is conferred by the ntK1000/K500 region, and R5020 enhanced binding of Pgr to the ntK800/K600 region of promoter I.f. Small interfering RNA knockdown of Pgr eliminated progesterone-dependent inhibition of aromatase mRNA and enzyme activity. Taken together, progesterone enhances recruitment of Pgr to specific regions of the promoter I.f of Cyp19a1 and regulates aromatase expression in hypothalamic neurons.

Original languageEnglish (US)
Pages (from-to)69-80
Number of pages12
JournalJournal of Molecular Endocrinology
Volume47
Issue number1
DOIs
StatePublished - Aug 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

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