Holterhus P M, Piefke S, Hiort O
Department of Pediatrics, Medical University of Lübeck, Germany.
J Steroid Biochem Mol Biol. 2002 Nov;82(4-5):269-75. doi: 10.1016/s0960-0760(02)00220-0.
Different androgens, e.g. virilizing androgens such as testosterone and its precursors as well as synthetic anabolic steroids, respectively, induce diverse biological effects. The molecular basis for this variety in biological actions, however, is not well understood. We hypothesized that this variability of actions may be due to steroid-specific target gene expression profiles following androgen receptor (AR)-activation. Therefore, we investigated androgen receptor dependent transactivation of three structurally different androgen responsive promoter constructs ((ARE)(2)TATA-luc, MMTV-luc, GRE-OCT-luc) in co-transfected Chinese hamster ovary (CHO)-cells as an artificial model simulating different natural target genes. Three virilizing androgens (dihydrotestosterone, testosterone, methyltrienolone), three anabolic steroids (oxandrolone, stanozolol, nandrolone) and two testosterone-precursors of gonadal and adrenal origin (dehydroepiandrosterone, androstenedione) were used as ligands (0.001-100 nM). All steroids proved to be potent activators of the AR. Remarkably, anabolic steroids and testosterone-precursors showed characteristic promoter activation profiles distinct from virilizing androgens with significantly lower (ARE)(2)TATA-luc activation. Hierarchical clustering based on similarity of activation profiles lead to a dendrogram with two major branches: first virilizing androgens, and second anabolics/testosterone-precursors. We conclude that steroid-specific differences in gene transcription profiles due to androgen receptor activation could contribute to differences in biological actions of androgens.
不同的雄激素，例如具有男性化作用的雄激素（如睾酮及其前体）以及合成代谢类固醇，分别会诱导出不同的生物学效应。然而，这种生物学作用多样性的分子基础尚未得到充分理解。我们推测，这种作用的变异性可能是由于雄激素受体（AR）激活后类固醇特异性的靶基因表达谱所致。因此，我们研究了在共转染的中国仓鼠卵巢（CHO）细胞中，三种结构不同的雄激素反应性启动子构建体（(ARE)(2)TATA-luc、MMTV-luc、GRE-OCT-luc）的雄激素受体依赖性反式激活，以此作为模拟不同天然靶基因的人工模型。使用了三种具有男性化作用的雄激素（双氢睾酮、睾酮、甲基三烯醇酮）、三种合成代谢类固醇（氧雄龙、司坦唑醇、诺龙）以及两种性腺和肾上腺来源的睾酮前体（脱氢表雄酮、雄烯二酮）作为配体（0.001 - 100 nM）。所有类固醇均被证明是AR的有效激活剂。值得注意的是，合成代谢类固醇和睾酮前体显示出与具有男性化作用的雄激素不同的特征性启动子激活谱，(ARE)(2)TATA-luc激活显著降低。基于激活谱相似性的层次聚类产生了一个具有两个主要分支的树状图：第一个是具有男性化作用的雄激素，第二个是合成代谢类固醇/睾酮前体。我们得出结论，雄激素受体激活导致的基因转录谱中的类固醇特异性差异可能有助于解释雄激素生物学作用的差异。
