Regulation of Normal and Malignant Prostate Growth by the Glucocorticoid Receptor

摘要

The glucocorticoid receptor (GR) is a hormone-dependent transcription factor involved in the regulation of a wide range of metabolic and developmental processes by controlling the expression of target genes in a hormone- and cell-specific manner. However, the expression and activity of GR in normal and malignant prostate growth is unclear. We have recently developed a GR phosphorylation site specific antibody to serine 211 of human GR (GR-S211- P) and found a strict correlation between phosphorylation of GR at this site and receptor transcriptional activity. Thus, GR phosphorylation at S211 is a surrogate marker for the ligand-bound and transcriptionally active form of GR in vivo. Using this antibody to survey GR phosphorylation in human tissues by immuohistochemistry, we came across the remarkable finding that ligand bound and transcriptionally active phospho-GR is present in the stroma and epithelium of normal prostate tissue,including basal and luminal epithelial cells. This was not the case for other tissues examined and suggests that the prostate is be continually exposed to glucocorticoids, such that GR is actively signaling in the prostate. The experiments described in this proposal are designed to elucidate the role of GR in prostate cell growth.