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Selective Modulation of Genomic and Nongenomic Androgen Responses by Androgen Receptor Ligands

LINDSEY B. LUTZ; MICHELLE JAMNONGJIT; WEI-HSIUNG YANG; DAVID JAHANI; ARVIND GILL; STEPHEN R. HAMMES
10/16/2014

Steroids can induce both transcription-dependent (genomic) and independent (nongenomic) signaling. Here, several classical androgen receptor ligands were tested for their bility to modulate genomic and nongenomic responses, focusing on the role of the oocyte-expressed Xenopus classical androgen receptor (XeAR) in mediating these  rocesses. Cellular fractionation and immunohistochemistry revealed that the XeAR was located throughout oocytes, including within the plasma membrane. RNA interference  nd oocyte maturation studies suggested that androgen-induced maturation was mediated in part by the XeAR in a transcription-independent fashion, perhaps by altering G  rotein-mediated signaling. While inducing minimal transcription in oocytes, all AR ligands promoted significant XeAR-mediated transcription in CV1 cells. In contrast, only  estosterone and androstenedione potently induced oocyte maturation, whereas dihydrotestosterone and R1881 actually inhibited testosterone and human chorionic gonadotropin-induced maturation and signaling. These results suggest that the nature of a steroidinduced signal (genomic vs. nongenomic) may depend on the type of target cell, the receptor location within cells, as well as the ligand itself. The identification of molecules capable of selectively altering genomic vs. nongenomic signaling may be useful in delineating the roles of these  athways in mediating androgen responses and might lead to the development of novel compounds that specifically modulate these signals in vivo. (Molecular Endocrinology 17:  106–1116, 2003)