IRS1 regulation by Wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype.
IRS1 regulation by Wnt/beta-catenin signaling and varied contribution of IRS1 to the neoplastic phenotype.
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DOI：
10.1074/jbc.m109.060319
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发表时间：
2010-01-15
期刊：
影响因子：
--
通讯作者：
Fearon ER
中科院分区：
文献类型：
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作者：
Bommer GT;Feng Y;Iura A;Giordano TJ;Kuick R;Kadikoy H;Sikorski D;Wu R;Cho KR;Fearon ER
β-连环蛋白水平的失调以及 β-连环蛋白/TCF（T 细胞因子）调节的基因表达的定位和组成性激活发生在许多癌症中，包括大多数结直肠癌和卵巢子宫内膜样腺癌的子集。基于基于微阵列的基因表达谱分析结果，我们发现胰岛素受体底物 1 (IRS1) 基因是大鼠肾上皮细胞系 RK3E 中 β-连环蛋白突变体、组成型活性形式异位表达时上调程度最高的基因之一。我们证明IRS1的表达可以被β-连环蛋白直接激活，可能部分通过β-连环蛋白/TCF与位于第一个内含子和IRS1转录起始位点下游的TCF共有结合元件结合。与β-连环蛋白是体内IRS1表达的重要调节因子的观点一致，我们观察到IRS1在许多具有β-连环蛋白组成性稳定的癌症中高表达，例如结直肠癌和卵巢子宫内膜样腺癌。使用短发夹RNA方法消除IRS1表达和功能，我们发现IRS1功能是RK3E细胞中β-连环蛋白有效从头肿瘤转化所必需的。我们的发现增加了越来越多的数据表明 IRS1 作为癌症发生和进展的关键信号成分。
Dysregulation of β-catenin levels and localization and constitutive activation of β-catenin/TCF (T cell factor)-regulated gene expression occur in many cancers, including the majority of colorectal carcinomas and a subset of ovarian endometrioid adenocarcinomas. Based on the results of microarray-based gene expression profiling we found the insulin receptor substrate 1 (IRS1) gene as one of the most highly up-regulated genes upon ectopic expression of a mutant, constitutively active form of β-catenin in the rat kidney epithelial cell line RK3E. We demonstrate expression of IRS1 can be directly activated by β-catenin, likely in part via β-catenin/TCF binding to TCF consensus binding elements located in the first intron and downstream of the IRS1 transcriptional start site. Consistent with the proposal that β-catenin is an important regulator of IRS1 expression in vivo, we observed that IRS1 is highly expressed in many cancers with constitutive stabilization of β-catenin, such as colorectal carcinomas and ovarian endometrioid adenocarcinomas. Using a short hairpin RNA approach to abrogate IRS1 expression and function, we found that IRS1 function is required for efficient de novo neoplastic transformation by β-catenin in RK3E cells. Our findings add to the growing body of data implicating IRS1 as a critical signaling component in cancer development and progression.