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This version published online on October 7, 2004
Endocrinology, doi:10.1210/en.2004-0871
A more recent version of this article appeared on January 1, 2005
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Submitted on July 8, 2004
Accepted on September 27, 2004

The androgen metabolite, 5{alpha}-androstane-3{beta}, 17{beta}-diol (3{beta}Adiol), is a potent modulator of estrogen receptor-{beta}1-mediated gene transcription in neuronal cells

Toni R. Pak*, Wilson C.J. Chung, Trent D. Lund, Laura R. Hinds, Colin M. Clay, and Robert J. Handa

Department of Biomedical Science, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523

* To whom correspondence should be addressed. E-mail: Toni.Pak{at}colostate.edu.

5{alpha}-androstane-3{beta}, 17{beta}-diol (3{beta}Adiol) is a metabolite of the potent androgen, 5{alpha}-dihydrotestosterone (DHT). Recent studies showed that 3{beta}Adiol binds to estrogen receptor-{beta} (ER{beta}) and regulates growth of the prostate gland through an estrogen, and not androgen, receptor-mediated pathway. These data raise the possibility that 3{beta}Adiol could regulate important physiological processes in other tissues that produce 3{beta}Adiol, such as the brain. Although it is widely accepted that the brain is a target for DHT action, there is no evidence that 3{beta}Adiol has a direct action in neurons. To explore the molecular mechanisms by which 3{beta}Adiol might act to modulate gene transcription in neuronal cells, we examined whether 3{beta}Adiol activates ER-mediated promoter activity and whether ER transactivation is facilitated by a classical ERE or an AP-1 complex. The HT-22 neuronal cell line was co-transfected with an expression vector containing ER{alpha}, ER-{beta}1, or the ER{beta} splice variant, ER-{beta}2 and one of two luciferase-reporter constructs containing either a consensus ERE or an AP-1 enhancer site. Cells were treated with 100 nM E2, 100 nM 3{beta}Adiol, or vehicle for 15 h. We show that 3{beta}Adiol activated ER-{beta}1-induced transcription mediated by an ERE equivalent to that of 17{beta}-estradiol (E2). By contrast, 3{beta}Adiol had no effect on ER{alpha} or ER-{beta}2-mediated promoter activity. Moreover, ER-{beta}1 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.
Key words: Estrogen Receptor-{beta}1 (ER-{beta}1) • 5{alpha}-androstane-3{beta} • 17{beta}-diol (3{beta}Adiol) • estrogen response element (ERE) • activator protein-1 (AP-1) • 17{beta}-estradiol (E2) • androgen




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