Stöcklin E, Wissler M, Gouilleux F, Groner B
Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.
Nature. 1996 Oct 24;383(6602):726-8. doi: 10.1038/383726a0.
Signal transduction pathways enable extracellular signals to activate latent transcription factors in the cytoplasm of cells. Dimerization, nuclear localization and binding to specific DNA sequences result in the induction of gene transcription by these proteins. These events are necessary for the functioning of the JAK/STAT pathway and of the glucocorticoid-receptor pathway. In the former, the protein Stat5, which is a member of a family of signal transducers and activators of transcription, is activated by cytokines, hormones and growth factors. These polypeptide ligands bind at the outside of the cell to specific transmembrane receptors and activate intracellular Janus protein tyrosine kinases (JAKs) to tyrosine-phosphorylate STAT proteins; interaction with the SH2 domain of the dimerization partner then confers the ability to bind to DNA at the STAT-response element and induce transcription. In the glucocorticoid-receptor pathway, the receptor interacts with its steroid hormone ligand in the cytoplasm, undergoes an allosteric change that enables the hormone receptor complex to bind to specific DNA-response elements (glucocorticoid response elements, or GRE) and modulate transcription. Although these pathways appear to be unrelated, we show here that the glucocorticoid receptor can act as a transcriptional co-activator for Stat5 and enhance Stat5-dependent transcription. Stat5 forms a complex with the glucocorticoid receptor which binds to DNA independently of the GRE. This complex formation between Stat5 and the glucocorticoid receptor diminishes the glucocorticoid response of a GRE-containing promoter.
信号转导通路能使细胞外信号激活细胞胞质中的潜在转录因子。二聚化、核定位以及与特定DNA序列的结合会导致这些蛋白质诱导基因转录。这些事件对于JAK/STAT通路和糖皮质激素受体通路的功能发挥是必需的。在前者中，转录信号转导子和激活子家族的成员蛋白Stat5被细胞因子、激素和生长因子激活。这些多肽配体在细胞外与特定的跨膜受体结合，并激活细胞内的Janus蛋白酪氨酸激酶（JAKs），使STAT蛋白酪氨酸磷酸化；然后与二聚化伴侣的SH2结构域相互作用，赋予其在STAT反应元件处结合DNA并诱导转录的能力。在糖皮质激素受体通路中，受体在细胞质中与其类固醇激素配体相互作用，发生变构变化，使激素受体复合物能够结合特定的DNA反应元件（糖皮质激素反应元件，或GRE）并调节转录。尽管这些通路看似不相关，但我们在此表明，糖皮质激素受体可作为Stat5的转录共激活因子并增强Stat5依赖性转录。Stat5与糖皮质激素受体形成一个独立于GRE结合DNA的复合物。Stat5与糖皮质激素受体之间的这种复合物形成会减弱含GRE启动子的糖皮质激素反应。
