Androgen regulation of transcription in the rat ventral prostate.

Abstract

The rat ventral prostate (RVP) has served as a model system for investigating steroid hormonal control of development and differentiation. This male specific organ is dependent on androgens for both its development and the maintenance of its normal secretory function. Androgen effects on the prostate are mediated through the androgen receptor (AR). In order to gain a better understanding of the molecular nature of androgen regulation in the RVP I have cloned the AR cDNA, mapped structural domains responsible for AR function, compared the level of transcription induction by the glucocorticoid receptor (GR) to that of the AR on several hormone response element (HRE) containing promoters, compared the strength and specificity of DNA binding by AR and GR, and established a panel of RVP epithelial cell lines that will be used to investigate androgen regulation in prostate cells. I have found that the AR is a member of the steroid receptor family of ligand dependent transcription regulatory proteins containing a structural organization similar the GR. AR binds to glucocorticoid response element (GRE) consensus DNA sequences with approximately a two-fold lower affinity than the GR and increases transcription from prostate and non-prostate expressed genes. AR does not require cell specific factors for its function; however, the level of transcription enhancement by AR on different genes varies compared to GR suggesting that gene specific and/or receptor specific proteins affect AR activity. Using the SV40 large T-antigen I have immortalized a panel of RVP epithelial cell lines. All of these cell lines maintain a morphology typical of RVP epithelial cells, express a nuclear localized T-antigen, tartrate inhibitable acid phosphatase, and the GR. The cell lines express a low level of the AR which can be complemented by introduction of the AR cDNA. I conclude that these cell lines most closely resemble RVP basal epithelial cells which may have been preferentially immortalized through transfecting primary cultures of epithelial cells. These cell lines will be used to further investigate the role of AR specific factors which allow androgen responses to prevail in the RVP.