Id2 is a target of the β-catenin/T cell factor pathway in colon carcinoma
Id2 is a target of the β-catenin/T cell factor pathway in colon carcinoma
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DOI：
10.1074/jbc.m107742200
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发表时间：
2001-11-30
影响因子：
4.8
通讯作者：
Phillips, WA
中科院分区：
文献类型：
--
作者：
Rockman, SP;Currie, SA;Phillips, WA
大肠腺瘤性息肉病（APC）和/或β -catenin基因突变导致β -catenin/T细胞因子（TCF）转录的激活发生在大多数结肠肿瘤中。越来越多的基因，包括c-myc和细胞周期蛋白D1，被认为是这一途径的靶点。我们现在报道，显性负螺旋-环-螺旋调节因子Id2也是结肠腺癌中β -catenin/TCF转录途径的靶标。对结肠癌细胞中Id2过表达机制的研究表明，Id2启动子被激活，Id2蛋白被β -catenin上调。相反，减少游离β -连环蛋白阻断了启动子活性的诱导。我们还使用了电泳迁移率转移试验和超转移来鉴定Id2启动子中与TCF4蛋白结合的基序。该基序的定点诱变消除了启动子报告子活性。在SW480细胞中转染Id2和在HT29结肠细胞中诱导Id2均可增加这些细胞的非锚定存活。越来越多的证据表明，Id2表达的破坏与肿瘤发生有关，我们的研究结果表明，Id2表达的失调是由于β -catenin/TCF途径的激活。
Activation of beta -catenin/T cell factor (TCF) transcription as a result of mutations in the adenomatous polyposis coli (APC) and/or beta -catenin genes occurs in the majority of colon tumors. An increasing number of genes, including c-myc and cyclin D1, have been implicated as targets of this pathway. We now report that the dominant negative helix-loop-helix regulator Id2 is also a target of the beta -catenin/TCF transcription pathway in colon adenocarcinoma. Investigation of the mechanism for the overexpression of Id2 in colon carcinoma cells demonstrated that the Id2 promoter is activated, and the Id2 protein is up-regulated by beta -catenin. Conversely, reducing free beta -catenin blocked this induction of promoter activity. We have also used an electrophoretic mobility shift assay and supershift to identify a motif in the Id2 promoter that binds to TCF4 protein. Site-directed mutagenesis of this motif abolished promoter reporter activity. Both transfection of Id2 into SW480 cells and induction of Id2 in HT29 colon cells was found to increase anchorage-independent survival of these cells. Growing evidence associates disruption to Id2 expression with tumorigenesis, and our findings suggest that this dysregulation of Id2 expression is due to the activation of the beta -catenin/TCF pathway.