The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors
The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors
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DOI：
10.1038/sj.onc.1202627
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发表时间：
1999-05-06
期刊：
影响因子：
8
通讯作者：
Matrisian, LM
中科院分区：
文献类型：
--
作者：
Crawford, HC;Fingleton, BM;Matrisian, LM
基质溶素是一种基质金属蛋白酶，在超过80%的肠腺瘤的肿瘤细胞中表达。这些肠肿瘤中的大多数与β-连环蛋白的积累有关，β-连环蛋白是钙粘蛋白粘附复合物的组分，并且通过其与T细胞因子（Tcf）DNA结合蛋白的结合，是Wnt信号转导途径中的调节剂。在小鼠肠道肿瘤中，基质溶素转录物显示出与β-连环蛋白的积累惊人的重叠。在结肠肿瘤细胞系中，基质溶素启动子以与β-连环蛋白/Tcf复合物的内源性水平成反比的方式被β-连环蛋白上调多达12倍，并且依赖于单个最佳Tcf-4识别位点。共表达的E-钙粘蛋白胞质结构域阻断了这种诱导，并降低了基础的启动子活性，在每一个结肠癌细胞系测试。Tcf结合位点的失活增加了启动子活性，而Tcf因子LEF-1的过表达显著下调了基质溶素启动子活性，这表明β-连环蛋白通过其消除Tcf介导的抑制的能力反式激活基质溶素启动子。由于遗传消融matrilysin减少多发性肠肿瘤（Min）小鼠的肿瘤形成，我们提出，β-连环蛋白积累的matrilysin生产的调节是肠道肿瘤发生的一个因素。
Matrilysin is a matrix metalloproteinase expressed in the tumor cells of greater than 80% of intestinal adenomas, The majority of these intestinal tumors are associated with the accumulation of beta-catenin, a component of the cadherin adhesion complex and, through its association with the T Cell Factor (Tcf) DNA binding proteins, a regulator in the Wnt signal transduction pathway. In murine intestinal tumors, matrilysin transcripts show striking overlap with the accumulation of beta-catenin protein, The matrilysin promoter is upregulated as much as 12-fold by beta-catenin in colon tumor cell lines in a manner inversely proportional to the endogenous levels of beta-catenin/Tcf complex and is dependent upon a single optimal Tcf-4 recognition site. Coexpression of the E-cadherin cytoplasmic domain blocked this induction and reduced basal promoter activity in every colon cancer cell line tested. Inactivation of the Tcf binding site increased promoter activity and overexpression of the Tcf factor, LEF-1, significantly downregulated matrilysin promoter activity, suggesting that beta-catenin transactivates the matrilysin promoter by virtue of its ability to abrogate Tcf-mediated repression. Because genetic ablation of matrilysin decreases tumor formation in multiple intestinal neoplasia (Min) mice, we propose that regulation of matrilysin production by beta-catenin accumulation is a contributing factor to intestinal tumorigenesis.