Bryant Winnifred, Snowhite Allison E, Rice Laurel W, Shupnik Margaret A
Department of Internal Medicine/Endocrinology, P.O. Box 800578, Health Sciences Center, University of Virginia, Charlottesville, Virginia 22908, USA.
Endocrinology. 2005 Feb;146(2):751-9. doi: 10.1210/en.2004-0825. Epub 2004 Nov 4.
Estrogen receptor (ER)alpha is a ligand-inducible transcription factor that mediates the physiological effects of 17beta-estradiol (E2). In the uterus, E2 is involved in tissue growth, maintenance, and differentiation. Delta5ERalpha (Delta5) is an ERalpha variant protein expressed in uterine tumors but not in normal tissue. We examined the transcriptional activity of Delta5 and its modulation of human ERalpha basal and E2-stimulated activity in Ishikawa cells, an endometrial cancer cell line. In transient transfection assays, Delta5 increased basal activity of an estrogen response element-containing promoter in the absence or presence of ERalpha but lessened stimulation by ERalpha and E2. Effects of Delta5 were not limited to model reporters, given that cyclin D1 and complement 3 promoters were similarly affected. Increases in basal transcription required dimerization and DNA binding of Delta5, whereas decreased E2 stimulation with ERalpha required only DNA binding. Decreased ligand stimulation was not unique to E2 but also applied to the selective ER modulators tamoxifen and genistein. However, promoter stimulation by epidermal growth factor is retained with Delta5. The ERalpha coactivator small nuclear ring finger protein is expressed in Ishikawa cells and uterine tumors, and it enhances effects of Delta5 alone and with ERalpha on basal activity of an estrogen response element reporter. Thus, in the presence of Delta5 plus ERalpha, there is a lower transcriptional response to E2 and SERMS, but stimulation by epidermal growth factor is retained. The expression of Delta5 in uterine carcinoma may provide a mechanism by which tumors could maintain expression of E2-responsive genes in the absence of E2.
雌激素受体（ER）α是一种配体诱导型转录因子，介导17β-雌二醇（E2）的生理效应。在子宫中，E2参与组织生长、维持和分化。Delta5ERα（Delta5）是一种在子宫肿瘤而非正常组织中表达的ERα变体蛋白。我们在子宫内膜癌细胞系 Ishikawa 细胞中检测了Delta5的转录活性及其对人ERα基础活性和E2刺激活性的调节作用。在瞬时转染实验中，Delta5在不存在或存在ERα的情况下均增加了含雌激素反应元件启动子的基础活性，但减弱了ERα和E2的刺激作用。Delta5的作用不仅限于模型报告基因，因为细胞周期蛋白D1和补体3启动子也受到类似影响。基础转录的增加需要Delta5的二聚化和DNA结合，而与ERα一起时E2刺激的减弱仅需要DNA结合。配体刺激的减弱并非E2所特有，也适用于选择性雌激素受体调节剂他莫昔芬和染料木黄酮。然而，表皮生长因子对启动子的刺激在Delta5存在时得以保留。ERα共激活因子小核环指蛋白在 Ishikawa 细胞和子宫肿瘤中表达，它增强了Delta5单独以及与ERα一起对雌激素反应元件报告基因基础活性的影响。因此，在存在Delta5加ERα的情况下，对E2和选择性雌激素受体调节剂的转录反应较低，但表皮生长因子的刺激得以保留。Delta5在子宫癌中的表达可能提供了一种机制，通过该机制肿瘤在缺乏E2的情况下仍可维持E2反应性基因的表达。
