Ankenbauer W, Strähle U, Schütz G
Institute of Cell and Tumor Biology, German Cancer Research Center, Heidelberg.
Proc Natl Acad Sci U S A. 1988 Oct;85(20):7526-30. doi: 10.1073/pnas.85.20.7526.
Modulation of gene expression by steroid hormones is mediated by receptor proteins that associate with regulatory elements of responsive genes upon binding the hormone ligand. The finding that two glucocorticoid responsive elements act cooperatively to stimulate transcription of the tyrosine aminotransferase gene prompted us to explore whether synergistic effects also occur when two different steroid hormone receptors are involved. A region of the chicken vitellogenin II gene that displays homologies to glucocorticoid and estradiol responsive elements was tested for its capability to confer estradiol and glucocorticoid inducibility to a heterologous promoter. When positioned immediately upstream of the thymidine kinase gene promoter, this element enhances expression by either steroid. Combination of both hormones results in a synergistic increase of transcription. Mutational analysis shows that sequences that show similarities of glucocorticoid and estradiol responsive elements are absolutely required for hormone induction. Analysis of the dose dependence of induction by both steroids demonstrates that half-maximal activity is observed at lower hormone concentrations when the other steroid is present in saturating amounts, which suggests that the synergistic induction observed with the combination of hormones is based on a functional interaction of the two hormone receptors.
类固醇激素对基因表达的调节是由受体蛋白介导的，这些受体蛋白在结合激素配体后与反应性基因的调控元件结合。两个糖皮质激素反应元件协同作用以刺激酪氨酸转氨酶基因转录这一发现促使我们探究当涉及两种不同的类固醇激素受体时是否也会出现协同效应。对鸡卵黄生成素II基因中与糖皮质激素和雌二醇反应元件具有同源性的一个区域进行了测试，以考察其赋予异源启动子雌二醇和糖皮质激素诱导性的能力。当该元件位于胸苷激酶基因启动子的紧邻上游时，两种类固醇激素均可增强其表达。两种激素联合使用会导致转录协同增加。突变分析表明，显示出与糖皮质激素和雌二醇反应元件相似性的序列对于激素诱导是绝对必需的。对两种类固醇激素诱导的剂量依赖性分析表明，当另一种类固醇激素以饱和量存在时，在较低激素浓度下可观察到半数最大活性，这表明激素联合使用时观察到的协同诱导是基于两种激素受体的功能相互作用。
