Cell type dependent regulation of multidrug resistance-1 gene expression by AML1-ETO
Cell type dependent regulation of multidrug resistance-1 gene expression by AML1-ETO
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DOI：
10.1016/j.bcmd.2007.05.005
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发表时间：
2007-11-01
影响因子：
2.3
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
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作者：
Hines, Robert;Boyapati, Anita;Zhang, Dong-Er
AML 1-ETO融合蛋白是由8;21染色体易位产生的，该易位通常在急性髓性白血病中鉴定。AML 1-ETO是一种DNA结合转录因子，已被证明在促进白血病发生中发挥关键作用。因此，明确AML 1-ETO基因表达调控的分子机制具有重要意义。在这里，我们报告说，AML 1-ETO对多药耐药-1（MDR 1）基因启动子的影响，一个已知的AML 1-ETO靶点，是高度细胞类型特异性的。除了先前报道的在C33 A和CV-1细胞中观察到MDR 1启动子的抑制外，AML 1-ETO在K562和B210细胞中强烈激活启动子。更重要的是，这种激活需要融合蛋白的AML 1和ETO部分，但不依赖于MDR 1启动子中的AML 1结合位点。此外，启动子缺失分析和染色质免疫沉淀试验的结果表明，这种激活效应可能是通过一般的转录机制，而不是启动子特异性因子的影响。基于这些数据，我们提出AML 1-ETO可能对基因表达产生相反的影响，这取决于细胞环境的各种条件。(C)2007年爱思唯尔公司All rights reserved.
The AML1-ETO fusion protein is generated from the 8;21 chromosome translocation that is commonly identified in acute myeloid leukemia. AML1-ETO is a DNA binding transcription factor and has been demonstrated to play a critical role in promoting leukemogenesis. Therefore, it is important to define the molecular mechanism of AML1-ETO in the regulation of gene expression. Here, we report that the effect of AML1-ETO on the promoter of multidrug resistance-1 (MDR1) gene, a known AML1-ETO target, is highly cell type specific. Besides observing repression of the MDR1 promoter in C33A and CV-1 cells as reported previously, AML1-ETO strongly activated the promoter in K562 and B210 cells. More importantly, this activation required both the AML1 and ETO portions of the fusion protein, but did not depend on the AML1 binding site in MDR1 promoter. Furthermore, results from promoter deletion analysis and chromatin immunoprecipitation assays suggested that this activation effect was likely through the influence of the general transcription machinery rather than promoter-specific factors. Based on these data, we propose that AML1-ETO may have opposing effects on gene expression depending on the various conditions of the cellular environment. (C) 2007 Elsevier Inc. All rights reserved.