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-Androstane-3ß, 17ß-Diol, Is a Potent Modulator of Estrogen Receptor-ß1-Mediated Gene Transcription in Neuronal Cells
Department of Biomedical Science, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523
Address all correspondence and requests for reprints to: Toni R. Pak, Department of Biomedical Sciences, College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado 80523. E-mail: toni.pak{at}colostate.edu.
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-Androstane-3ß, 17ß-diol (3ßAdiol) is a metabolite of the potent androgen, 5-dihydrotestosterone. Recent studies showed that 3ßAdiol binds to estrogen receptor (ER)-ß and regulates growth of the prostate gland through an estrogen, and not androgen, receptor-mediated pathway. These data raise the possibility that 3ßAdiol could regulate important physiological processes in other tissues that produce 3ßAdiol, such as the brain. Although it is widely accepted that the brain is a target for 5-dihydrotestosterone action, there is no evidence that 3ßAdiol has a direct action in neurons. To explore the molecular mechanisms by which 3ßAdiol might act to modulate gene transcription in neuronal cells, we examined whether 3ßAdiol activates ER-mediated promoter activity and whether ER transactivation is facilitated by a classical estrogen response element (ERE) or an AP-1 complex. The HT-22 neuronal cell line was cotransfected with an expression vector containing ER, ER-ß1, or the ERß splice variant, ER-ß2 and one of two luciferase-reporter constructs containing either a consensus ERE or an AP-1 enhancer site. Cells were treated with 100 nM 17ß-estradiol, 100 nM 3ßAdiol, or vehicle for 15 h. We show that 3ßAdiol activated ER-ß1-induced transcription mediated by an ERE equivalent to that of 17ß-estradiol. By contrast, 3ßAdiol had no effect on ER- or ER-ß2-mediated promoter activity. Moreover, ER-ß1 stimulated transcription mediated by an ERE and inhibited transcription by an AP-1 site in the absence of ligand binding. These data provide evidence for activation of ER signaling pathways by an androgen metabolite in neuronal cells.
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