Interference between progesterone and dioxin signal transduction pathways - Different mechanisms are involved in repression by the progesterone receptor A and B isoforms
Interference between progesterone and dioxin signal transduction pathways - Different mechanisms are involved in repression by the progesterone receptor A and B isoforms
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DOI：
10.1074/jbc.273.15.8829
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发表时间：
1998-04-10
影响因子：
4.8
通讯作者：
van der Burg, B
中科院分区：
文献类型：
--
作者：
Kuil, CW;Brouwer, A;van der Burg, B
转录因子之间的相互作用是调节基因转录的重要手段，导致基因表达模式和细胞命运的改变。在这项研究中，我们报告，孕激素受体（PR）可以强烈干扰T47 D乳腺癌细胞中的芳香烃受体（AhR）介导的反式激活。这种干扰不仅表现为诱导转染的二恶英响应报告质粒，但也对AhR介导的内源性细胞色素P450- 1A 1活性的上调。干扰是不相互的，作为2，3，7，8-四氯二苯并-p-二恶英（TCDD），最有效的激活剂的AhR，不抑制孕激素诱导的启动子活性。当人PR的同种型hPR-A和hPR-B分别在HepG-2肝癌细胞中表达时，两者均负干扰AhR信号传导，表明该作用不限于T47 D细胞。此外，从抗孕激素和突变体受体的研究中获得的结果表明，两种PR亚型的潜在抑制分子机制存在差异，hPR-A的抑制不需要额外的基因表达或受体的完全转录活性构象。然而，对于hPR-B的抑制作用，似乎涉及额外的基因表达，因为只有激动剂结合的野生型hPR-B可以清楚地抑制TCDD诱导的反应。总之，这些研究突出了不同的机制的镇压孕激素受体亚型的AhR介导的反式激活和强调的重要性，不同家族的转录因子之间的相互作用，在基因转录的调节。
Interactions between transcription factors are an important means of regulating gene transcription, leading to modifications in the pattern of gene expression and cell fate. In this study, we report that the progesterone receptor (PR) can strongly interfere with transactivation mediated by the arylhydrocarbon receptor (AhR) in T47D breast cancer cells. This interference was not only demonstrated by induction of a transfected dioxin-responsive reporter plasmid but also on the AhR-mediated up-regulation of the endogenous cytochrome P450-1A1 activity. The interference was not mutual, as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent activator of the AhR, did not inhibit progestin-induced promoter activity. When the isoforms of the human PR, hPR-A and hPR-B, were expressed separately in HepG-2 hepatocarcinoma cells, both negatively interfered with the AhR signaling, indicating that the effect is not restricted to T47D cells. In addition, results obtained from studies with both antiprogestins and mutant receptors indicate differences in the underlying molecular mechanisms of repression for both PR isoforms, The suppression by hPR-A does not require additional gene expression or a full transcriptional competent conformation of the receptor. For the repressive effects of hPR-B, however, additional gene expression seems to be involved, as only the agonist-bound, wild-type hPR-B could clearly repress the TCDD-induced response. In conclusion, these studies highlight different mechanisms of repression for the progesterone receptor isoforms on the AhR-mediated trans-activation and underscore the importance of interactions between transcription factors of different families in the regulation of gene transcription.