Uht R M, Anderson C M, Webb P, Kushner P J
Department of Pathology, School of Medicine, University of California at San Francisco, 94143, USA.
Endocrinology. 1997 Jul;138(7):2900-8. doi: 10.1210/endo.138.7.5244.
Estrogens and glucocorticoids often act in opposition to regulate physiological responses. We investigated whether this might reflect the opposing actions of hormone-bound receptors on target genes regulated by the AP-1 response element. We performed a series of transfection experiments in which transcriptional activation, mediated by the AP-1 response element, was reflected in reporter gene activity. As previously described, we found that estrogens stimulate, whereas the glucocorticoid dexamethasone (Dex) inhibits, transcription through a model promoter from the collagenase gene (-73 to +63). This promoter bears a consensus AP-1 response element. When HeLa cells were treated with both estradiol and Dex, the steroids counteracted each other's transcriptional effects. The amount of transfected estrogen and glucocorticoid receptors (ER and GR) determined the extent to which Dex blunted estrogen stimulation or estrogen prevented Dex inhibition. The ER/GR interaction was observed both in the presence of estradiol and tamoxifen, which has previously been shown to have estrogen-like action at an AP-1 response element. The AP-1 family member c-Jun enhanced Dex inhibition and estradiol stimulation of transcriptional activation. c-Fos potentiated the effect of cotransfected c-Jun on estradiol stimulation but not Dex inhibition. The pattern of steroid responses was retained in the presence of the c-Jun activator phorbol 12-myristate 13-acetate. However, estradiol stimulation was lost in the presence of the c-Jun activator tumor necrosis factor-alpha. The ER/GR/AP-1 response element interaction was present, not only in a cell line originally derived from a uterine cervical adenocarcinoma (HeLa), but also in a cell line derived from the hypothalamus (GT1-1). Lastly, both progesterone receptor types A and B also interacted with the ER at the AP-1 site. These data indicate that opposing steroid influences can be mediated at the level of transcription through the AP-1 site and suggest that the integration of hormone action at this response element may underlie some of the opposing actions of estrogens and glucocorticoids or progestins on physiological responses.
雌激素和糖皮质激素常常发挥相反作用来调节生理反应。我们研究了这是否可能反映了激素结合受体对由AP-1反应元件调控的靶基因的相反作用。我们进行了一系列转染实验，其中由AP-1反应元件介导的转录激活通过报告基因活性得以体现。如先前所述，我们发现雌激素具有刺激作用，而糖皮质激素地塞米松（Dex）则通过胶原酶基因（-73至+63）的模型启动子抑制转录。该启动子带有一个共有AP-1反应元件。当用雌二醇和Dex同时处理HeLa细胞时，这两种类固醇相互抵消了对方的转录效应。转染的雌激素和糖皮质激素受体（ER和GR）的量决定了Dex减弱雌激素刺激或雌激素阻止Dex抑制的程度。在存在雌二醇和他莫昔芬的情况下均观察到了ER/GR相互作用，先前已表明他莫昔芬在AP-1反应元件处具有类似雌激素的作用。AP-1家族成员c-Jun增强了Dex对转录激活的抑制作用以及雌二醇的刺激作用。c-Fos增强了共转染的c-Jun对雌二醇刺激的作用，但对Dex抑制作用无增强效果。在存在c-Jun激活剂佛波酯12-肉豆蔻酸酯13-乙酸酯的情况下，类固醇反应模式得以保留。然而，在存在c-Jun激活剂肿瘤坏死因子-α的情况下，雌二醇刺激作用消失。ER/GR/AP-1反应元件相互作用不仅存在于最初源自子宫颈腺癌的细胞系（HeLa）中，也存在于源自下丘脑的细胞系（GT1-1）中。最后，A、B两种类型的孕激素受体也在AP-1位点与ER相互作用。这些数据表明，相反的类固醇影响可通过AP-1位点在转录水平上介导，并且提示在该反应元件处激素作用的整合可能是雌激素和糖皮质激素或孕激素对生理反应的一些相反作用的基础。
