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UBC Theses and Dissertations

Regulation of androgen action by sex hormone-binding globulin Hong, Eui-ju


Sex hormone-binding globulin (SHBG) binds androgens and estrogens with high affinity, and regulates the distribution of these sex steroids in the blood and other biological fluids. Liver is the primary site of SHBG production, but the human SHBG transcription unit responsible for this is also expressed in proximal convoluted tubule (PCT) epithelial cells in a transgenic mouse model. Unlike hepatocytes which actively secrete SHBG and retain little immunoreactive SHBG within their cytoplasm, an incompletely glycosylated SHBG isoform has been found to accumulate inside PCT cells. These cells are androgen target cells, and the presence of SHBG within them accentuates androgen-dependent regulation of gene expression mediated by the androgen receptor (AR). The retention and accumulation of SHBG within cells involves an interaction with the intracellular 37-kDa laminin receptor precursor (LRP), which was identified as a SHBG interacting-protein using yeast hybrid screen. This interaction was confirmed by Glutathione S-transferase pull-down assays, and was prevented by mutating the LRP laminin-binding site. Human SHBG was found to co-localize LRP in the peri-nuclear location of renal epithelial cells of transgenic mice and SHBG:LRP complexes were observed within the endoplasmic reticulum of these cells by immunoprecipitation assay. These data suggest that a physical interaction between SHBG and LRP contributes to the intracellular trapping of an incompletely glycosylated SHBG in PCT cells and an increase in AR-mediated androgen action. Since human SHBG transcripts have been reported in prostate cancer cells, we examined whether SHBG in the extracellular environment or the cytoplasm of human LNCaP prostate cancer cells influences their response to androgens. Although human SHBG is cleaved into two laminin G-like (LG) domains by kallikrein-related peptidase 4, this does not change its steroid-binding activity. Furthermore, the amino-terminal SHBG LG domiain induced AR-mediated androgen activity in LNCaP cells in the same way as intact SHBG. Although immunoreactive SHBG was not detected within LNCaP cells, siRNA-mediated knockdown of SHBG transcripts decreased AR-dependent inceases in prostate-specific antigen mRNA levels and androgen-reporter gene activity. These data suggest that while SHBG in LNCaP cell medium limits the metabolic clearance of androgens, SHBG within these cells enhances AR-induced gene expression.

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