Estrogen's effects on mitochondrial gene expression - Mechanisms and potential contributions to estrogen carcinogenesis
Estrogen's effects on mitochondrial gene expression - Mechanisms and potential contributions to estrogen carcinogenesis
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DOI：
10.1196/annals.1322.030
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Yager, JD
中科院分区：
文献类型：
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作者：
Chen, JQ;Yager, JD
雌激素受体(ER)a和事件相关蛋白(ERP)定位于细胞核，参与17β雌二醇(E_2)对核内雌激素反应基因的调控。此外，最近的研究表明，ERα与E2结合后，定位于质膜，启动丝裂原活化蛋白激酶(MAPK)介导的信号转导。此前，我们报道了在肝脏、培养的大鼠肝细胞和人HepG2细胞中，雌激素处理提高了线粒体DNA(MtDNA)编码基因的转录水平。这些作用被一种特定的抗雌激素阻断，这表明内质网起到了作用。其他人则报告了线粒体DNA中存在可能的雌激素反应元件。这些观察表明，内质网定位于线粒体，并直接作用于提高mtDNA编码的转录本的水平，类似于已观察到的糖皮质激素受体。利用Western印迹分析、共聚焦免疫荧光、免疫金电子显微镜和凝胶电泳法，我们证明了雌激素依赖的人乳腺癌细胞HepG2和MCF-7的线粒体中存在ERP和ERα。综上所述，这些结果提示内质网可能作为转录因子直接参与E2对mtDNA转录的调控。
Estrogen receptor (ER)a and ERP are localized in the nucleus and involved in the regulation of nuclear estrogen-responsive genes by 17 beta estradiol (E2). In addition, recently others have shown that upon E2 binding, ER alpha localizes to the plasma membrane and initiates mitogen-activated protein kinase (MAPK)-mediated signal transduction. Previously, we reported that in liver, cultured rat hepatocytes and human HepG2 cells, estrogen treatment enhanced mitochondrial DNA (mtDNA)-encoded gene transcript levels. These effects were blocked by a specific antiestrogen, suggesting a role for the ER. Others have reported the presence of putative estrogen- responsive elements in mtDNA. These observations suggested the hypothesis that the ER localized in mitochondria and functioned directly to enhance the levels of mtDNA-encoded transcripts, analogous to what has been observed for the glucocorticoid hormone receptor. Using Western blot analysis, confocal immunofluorescence, immunogold electron microscopy, and gel electrophoresis mobility shift assays, we have demonstrated the estrogen-dependent presence of ERP and ER alpha within mitochondria of HepG2 and MCF-7 human breast tumor cells. Together, these results suggest that the ERs may act as transcription factors directly involved in the regulation by E2 of mtDNA transcription.