Transcriptional activation of c-myc proto-oncogene by WT1 protein
Transcriptional activation of c-myc proto-oncogene by WT1 protein
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DOI：
10.1038/sj.onc.1207609
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发表时间：
2004-09-09
期刊：
影响因子：
8
通讯作者：
Minden, MD
中科院分区：
文献类型：
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作者：
Han, YQ;San-Marina, S;Minden, MD
Wilms‘s Tumor 1基因(WT1)在泌尿生殖系统发育和恶性肿瘤中起重要作用。通过DNA结合，WT1可以增强或抑制转录，这取决于DNA结合位点的上下文或表达它的细胞类型。WT1在多种人类癌症中过表达，包括白血病和乳腺癌；在这些疾病中，WT1的表达与预后不良有关。为了确定WT1如何影响乳腺癌细胞中c-myc的表达，我们在体内检测了乳腺癌细胞中内源性和外源性WT1蛋白与c-myc启动子结合的能力。利用c-myc启动子驱动的荧光素酶构建，我们发现不同形式的WT1可以增强报告基因的表达。与其他研究中WT1被报道为c-myc的负调节因子不同，我们发现WT1的-和+KTS形式都可以增强c-myc的表达，这取决于细胞类型。CMYC启动子第二个主要转录起始点附近的WT1结合位点被证实参与WT1上调人c-myc基因。最后，我们证明WT1的过表达诱导了乳腺癌细胞内源性c-myc蛋白丰度的显著增加，这与WT1诱导后c-myc转录上调是一致的。这些观察结果有力地证明，在乳腺癌的案例中，WT1在一定程度上是通过刺激c-myc的表达来发挥癌基因的作用。
The Wilms' tumor 1 gene (WT1) plays an essential role in urogenital development and malignancy. Through DNA binding, WT1 can either enhance or repress transcription depending on the context of the DNA-binding sites or the cell type in which it is expressed. WT1 is overexpressed in a variety of human cancers, including leukemia and breast cancer; in these diseases, the expression of WT1 is associated with a poor prognosis. To determine how WT1 affects c-myc expression in the context of breast cancer cells, we have examined the ability of both endogenous and exogenous WT1 proteins in breast cancer cells to bind to the c-myc promoter in vivo. Using c-myc-promoter-driven luciferase constructs, we found that different forms of WT1 could enhance the expression of the reporter. Unlike other studies where WT1 is reported to be a negative regulator of c-myc, we found that both the - and + KTS forms of WT1 could act to enhance c-myc expression, depending on the cell type. The WT1-binding site near the second major transcription start site of the cmyc promoter was confirmed to be involved in upregulation of human c-myc by WT1. Finally, we demonstrated that overexpression of WT1 induced a significant increase in the abundance of endogenous c-myc protein in breast cancer cells, consistent with the upregulation of c-myc transcription following WT1 induction. These observations strongly argue that in the case of breast cancer WT1 is functioning as an oncogene in part by stimulating the expression of c-myc.