Session: MON 355-388-Sex Hormone Receptor Action & Reaction
Poster Board MON-369
Previously, we identified androgen responsive genes (ARGs) in HPr-1AR human prostate epithelial cells. Our objective here was to identify ARGs in prostate epithelial cells that control cell proliferation, and to investigate the mechanisms through which AR regulates their expression. We examined the effects of androgens on cell proliferation and found that DHT inhibited HPr-1AR cell proliferation, increasing the doubling time of these cells more than 2-fold. Cell cycle analysis by flow cytometry revealed an increase in the number of cells in G1 and a decrease in the number of cells in S phase and G2, indicating a prolonged G1 interval. In the cell cycle, G1 to S phase progression is initiated by Cyclin D and Cyclin-dependent kinase (Cdk) gene products, which together form a complex crucial for relief of Rb-mediated growth suppression and expression of S phase promoting genes. We examined the expression of critical cell cycle regulators using quantitative real-time PCR. Cyclin D and Cdk mRNAs were indeed androgen-repressed, and down-regulation of these mRNAs was AR-dependent. Remarkably, Cyclin D1 mRNA was destabilized and exhibited a shorter half-life following androgen treatment. Although Cyclin D2 mRNA stability was unchanged by androgen, nascent transcripts of Cyclin D2 were androgen-repressed, implicating transcriptional repression by AR in the down-regulation of Cyclin D2. Taken together, these results suggest that AR-mediated inhibition of HPr-1AR cell proliferation by androgens involves down-regulation of Cyclin D-Cdk complexes and through transcriptional repression of Cyclin D2 mRNA and/or destabilization of Cyclin D1 mRNA. Our findings provide insight into the mechanisms of transcriptional regulation operating within hormone-responsive gene networks, which modulate the physiologic and pathologic effects or hormones in the body.
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