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首页> 外文期刊>Molecular and Cellular Biology >A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene.
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A retinoic acid response element that overlaps an estrogen response element mediates multihormonal sensitivity in transcriptional activation of the lactoferrin gene.

机译：与雌激素响应元件重叠的视黄酸响应元件在乳铁蛋白基因的转录激活中介导多激素敏感性。

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The lactoferrin gene is highly expressed in many different tissues, and its expression is controlled by different regulators. In this report, we have defined a retinoic acid response element (RARE) in the 5'-flanking region of the lactoferrin gene promoter. The lactoferrin-RARE is composed of two AGGTCA-like motifs arranged as a direct repeat with 1-bp spacing (DR-1). A gel retardation assay demonstrated that it bound strongly with retinoid X receptor (RXR) homodimers and RXR-retinoic acid receptor (RAR) heterodimers as well as chicken ovalbumin upstream promoter transcription factor (COUP-TF) orphan receptor. In CV-1 cells, the lactoferrin-RARE linked with a heterologous thymidine kinase promoter was strongly activated by RXR homodimers in response to 9-cis-retinoic acid (9-cis-RA) but not to all-trans-RA. When the COUP-TF orphan receptor was cotransfected, the 9-cis-RA-induced RXR homodimer activity was strongly repressed. A unique feature of the lactoferrin-RARE is that it has an AGGTCA-like motif in common with an estrogen-responsive element (ERE). The composite RARE/ERE contributes to the functional interaction between retinoid receptors and the estrogen receptor (ER) and their ligands. In CV-1 cells, cotransfection of the retinoid and estrogen receptors led to mutual inhibition of the other's activity, while an RA-dependent inhibition of ER activity was observed in breast cancer cells. Furthermore, the lactoferrin-RARE/ERE showed differential transactivation activity in different cell types. RAs could activate the lactoferrin-RARE/ERE in human leukemia HL-60 cells and U937 cells but not in human breast cancer cells. By gel retardation analyses, we demonstrated that strong binding of the endogenous COUP-TF in breast cancer cells to the composite element contributed to diminished RA response in these cells. Thus, the lactoferrin-RARE/ERE functions as a signaling switch module that mediates multihormonal responsiveness in the regulation of lactoferrin gene expression.
机译：乳铁蛋白基因在许多不同的组织中高度表达，其表达受不同的调节剂控制。在此报告中，我们在乳铁蛋白基因启动子的5'侧翼区域定义了维甲酸响应元件（RARE）。乳铁蛋白-RARE由两个AGGTCA样基序组成，它们以1 bp的间隔（DR-1）直接重复排列。凝胶阻滞试验表明，它与类维生素A X受体（RXR）同二聚体和RXR-视黄酸受体（RAR）异二聚体以及鸡卵清蛋白上游启动子转录因子（COUP-TF）孤儿受体牢固结合。在CV-1细胞中，与异源胸苷激酶启动子连接的乳铁蛋白RARE被RXR同型二聚体强烈激活，以响应9-顺-视黄酸（9-cis-RA），但不响应全反式-RA。当COUP-TF孤儿受体被共转染时，强烈抑制9-顺式-RA诱导的RXR同型二聚体活性。乳铁蛋白-RARE的独特之处在于，它具有与雌激素响应元件（ERE）相同的AGGTCA样基序。复合RARE / ERE有助于类维生素A受体与雌激素受体（ER）及其配体之间的功能相互作用。在CV-1细胞中，类维生素A和雌激素受体的共转染导致相互抑制对方的活性，而在乳腺癌细胞中观察到了RA依赖性的ER活性抑制。此外，乳铁蛋白-RARE / ERE在不同细胞类型中表现出不同的反式激活活性。 RA可以激活人白血病HL-60细胞和U937细胞中的乳铁蛋白-RARE / ERE，但不能激活人乳腺癌细胞。通过凝胶阻滞分析，我们证明乳腺癌细胞中内源性COUP-TF与复合元素的强结合有助于减少这些细胞中的RA反应。因此，乳铁蛋白-RARE / ERE充当信号转导模块，在乳铁蛋白基因表达的调节中介导多激素反应。

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