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Regular article |
a Departments of Obstetrics and Gynecology,
b Cell Biology,
c Urologic Surgery, and
d Center for Reproductive Biology Research, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232-2633
e The Prostate Centre, Jack Bell Research Centre, Vancouver, British Columbia V6H 3Z6, Canada
ABSTRACT
The epididymis provides the optimal milieu for sperm maturation and storage. Epididymal secretory proteins are believed to be involved in that process. Androgens are the major endocrine and paracrine regulatory signals that regulate gene expression in the epididymis. We have previously identified an androgen-dependent retinoic acid-binding protein (mE-RABP) that is secreted into the luminal fluid from the mouse mid/distal caput epididymidis. The mE-RABP protein belongs to the lipocalin superfamily and may be involved in the trafficking of retinoic acid within the epididymis. We have recently demonstrated that 5 kilobases of the 5' flanking region of the mE-RABP gene contained all the information for the hormonal regulation and the tissue-, region-, and cell-specific expression of the mE-RABP gene. In this study, we have identified a complex androgen-specific response region (ARR) within the first 600 base pairs of the mE-RABP gene promoter. Androgen (DHT) but not glucocorticoid (DEX) activates the ARR in HeLa and PC-3 cells. Two androgen receptor binding sites have been located at positions -445/-459 and -102/-88 and were named ARBS-1 and ARBS-0, respectively. Point mutations of ARBS-0 resulted in a slight decrease of the androgen response. However, mutations of ARBS-1 led to a total loss of the androgen responsiveness, suggesting that it was a major cis-acting element. When ARBS-1 is isolated from its promoter context, it serves as a weak androgen-responsive element that was activated by both androgens and glucocorticoids. Also, the -543/-88 DNA promoter fragment behaved as a poor androgen-responsive region, suggesting that regulatory elements located within the proximal mE-RABP promoter were required for a full androgen response. In conclusion, the mE-RABP ARR is a good model for the study of molecular mechanisms that lead to an androgen-specific responsiveness in vivo.
First decision: 20 March 2000.
1 This work was supported by NIH grants HD03820, HD05797, HD36900, and HD25206.
2 Correspondence: Marie-Claire Orgebin-Crist, Center for Reproductive Biology Research, Vanderbilt University, School of Medicine, Medical Center North, Room C-3306, Nashville, TN 37232-2633. FAX: 615 343 7797; m-c.orgebin-crist{at}mcmail.vanderbilt.edu
3 Current address: Institut National de la Recherche Agronomique, Station Commune de recherches en Ichtyophysiologie, Biodiversite et Environnement, Campus de Beaulieu, 35042 Rennes Cedex, France.
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