5α-Androstane-3β, 17β-diol (3βAdiol) is a metabolite of the potent androgen, 5α-dihydrotestosterone. Recent studies showed that 3βAdiol binds to estrogen receptor (ER)-β and regulates growth of the prostate gland through an estrogen, and not androgen, receptor-mediated pathway. These data raise the possibility that 3βAdiol could regulate important physiological processes in other tissues that produce 3βAdiol, such as the brain. Although it is widely accepted that the brain is a target for 5α-dihydrotestosterone action, there is no evidence that 3βAdiol has a direct action in neurons. To explore the molecular mechanisms by which 3βAdiol might act to modulate gene transcription in neuronal cells, we examined whether 3βAdiol 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 ERα, ER-β1, or the ERβ splice variant, ER-β2 and one of two luciferase-reporter constructs containing either a consensus ERE or an AP-1 enhancer site. Cells were treated with 100 nM 17β-estradiol, 100 nM 3βAdiol, or vehicle for 15 h. We show that 3βAdiol activated ER-β1-induced transcription mediated by an ERE equivalent to that of 17β-estradiol. By contrast, 3βAdiol had no effect on ERα- or ER-β2-mediated promoter activity. Moreover, ER-β1 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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