Gordon D A, Chamberlain N L, Flomerfelt F A, Miesfeld R L
Department of Biochemistry, University of Arizona, Tucson 85721, USA.
Exp Cell Res. 1995 Apr;217(2):368-77. doi: 10.1006/excr.1995.1099.
The androgen (AR) and glucocorticoid receptors (GR) are related ligand-activated transcriptional regulators which bind the same cis-acting element and are coexpressed in a variety of cell types. Despite a shared DNA binding site, these receptors mediate diverse cellular responses. To explain this paradox, the existence of cell-specific factors that interact with, and modulate the function of, distinct receptors has been proposed. Prostate epithelial cell growth is sensitive to androgens, but is not affected by glucocorticoids, even though both AR and GR are expressed in these cells. We have recently isolated a unique panel of prostate epithelial cell lines from normal rats and have used these cell lines to examine cell-specific steroid responses. In this study, we compared the abilities of AR and GR to enhance transcription of several different reporter genes regulated by simple (i.e., noncompsite) hormone response elements (HREs) in prostate and nonprostate cell lines. The cell-specific effect occurred independently of the AR hormone binding domain and could be observed with a GAL4 fusion protein containing only the AR N-terminal regulatory domain. Gel shift analyses showed that the relative DNA binding affinity of AR for a probe containing a simple HRE was similar in prostate and nonprostate cell extracts. Presently, the only factors known to mediate steroid receptor-specific gene regulation are cJun and cFos, but there were no cell-specific differences in the functional levels of these proteins which could account for a preferential effect on AR-dependent transcription. Taken together, these results suggest that cell-specific activities exist which can preferentially modulate transcriptional transactivation by AR.
雄激素受体（AR）和糖皮质激素受体（GR）是相关的配体激活转录调节因子，它们结合相同的顺式作用元件，并在多种细胞类型中共同表达。尽管有共同的DNA结合位点，但这些受体介导不同的细胞反应。为了解释这一矛盾现象，有人提出存在与不同受体相互作用并调节其功能的细胞特异性因子。前列腺上皮细胞的生长对雄激素敏感，但不受糖皮质激素影响，尽管AR和GR在这些细胞中均有表达。我们最近从正常大鼠中分离出一组独特的前列腺上皮细胞系，并利用这些细胞系研究细胞特异性类固醇反应。在本研究中，我们比较了AR和GR增强前列腺和非前列腺细胞系中由简单（即非复合）激素反应元件（HRE）调控的几种不同报告基因转录的能力。细胞特异性效应独立于AR激素结合域发生，并且在仅含有AR N端调节域的GAL4融合蛋白中也能观察到。凝胶迁移分析表明，在前列腺和非前列腺细胞提取物中，AR对含有简单HRE的探针的相对DNA结合亲和力相似。目前，已知介导类固醇受体特异性基因调控的唯一因子是cJun和cFos，但这些蛋白质的功能水平在细胞间没有差异，无法解释对AR依赖性转录的优先效应。综上所述，这些结果表明存在细胞特异性活性，可优先调节AR的转录反式激活作用。
