摘要

       雄激素受体 (AR) 通过与影响 AR 靶基因转录的基因组雄激素反应元件 (ARE) 结合，介导雄激素的生理和病理生理作用，包括性分化、前列腺发育和癌症进展。 ARE 的组成和背景因基因而异，因此使 AR 能够在单个细胞核内赋予多种调节功能。我们使用永生化人前列腺上皮细胞系的表达谱来鉴定 205 个雄激素反应基因 (ARG)，其中大多数是新的。此外，我们进行了染色质免疫沉淀以识别 524 个 AR 结合区域，并在报告基因检测中验证了几个此类区域的 ARE 活性。有趣的是，我们 67% 的 ARE 位于我们 84% 的 ARG 转录起始位点的约 50 kb 内。事实上，大多数 ARG 与两个或多个 ARE 相关，并且 ARG 本身有时连接在包含多达 13 个 ARE 和 12 个 ARG 的基因簇中。 ARE 通常是复合元件，包含与其他转录调节因子的结合基序相邻的 AR 结合序列。在功能上，ARG 通常参与前列腺细胞增殖、通讯、分化和可能的癌症进展。我们的研究结果为雄激素反应基因网络转录调控的细胞和基因特异性机制提供了新的见解。

       The androgen receptor (AR) mediates the physiologic and pathophysiologic effects of androgens including sexual differentiation, prostate development, and cancer progression by binding to genomic androgen response elements (AREs), which influence transcription of AR target genes. The composition and context of AREs differ between genes, thus enabling AR to confer multiple regulatory functions within a single nucleus. We used expression profiling of an immortalized human prostate epithelial cell line to identify 205 androgen-responsive genes (ARGs), most of them novel. In addition, we performed chromatin immunoprecipitation to identify 524 AR binding regions and validated in reporter assays the ARE activities of several such regions. Interestingly, 67% of our AREs resided within ∼50 kb of the transcription start sites of 84% of our ARGs. Indeed, most ARGs were associated with two or more AREs, and ARGs were sometimes themselves linked in gene clusters containing up to 13 AREs and 12 ARGs. AREs appeared typically to be composite elements, containing AR binding sequences adjacent to binding motifs for other transcriptional regulators. Functionally, ARGs were commonly involved in prostate cell proliferation, communication, differentiation, and possibly cancer progression. Our results provide new insights into cell- and gene-specific mechanisms of transcriptional regulation of androgen-responsive gene networks.

http://genesdev.cshlp.org/content/21/16/2005.short