Functional significance of type 1 insulin-like growth factor-mediated nuclear translocation of the insulin receptor substrate-1 and β-catenin
Functional significance of type 1 insulin-like growth factor-mediated nuclear translocation of the insulin receptor substrate-1 and β-catenin
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DOI：
10.1074/jbc.m504516200
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发表时间：
2005-08-19
影响因子：
4.8
通讯作者：
Baserga, R
中科院分区：
文献类型：
--
作者：
Chen, J;Wu, A;Baserga, R
以前的工作表明，当细胞受到1型胰岛素样生长因子(IGF-1)的刺激时，转录调节因子β-连环蛋白可以移位到细胞核。我们通过免疫共沉淀和共聚焦显微镜显示，β-连环素与胰岛素受体底物-1(IRS-1)结合并共同定位，IRS-1是胰岛素和IGF-1受体的对接蛋白。IGF-1介导的β-连环蛋白的核转位需要IRS-1，导致β-连环蛋白靶基因的激活。IGF-1介导的β-连环蛋白的核转位是通过IRS-1的核转位来促进的。IRS-1和β-连环蛋白都被招募到细胞周期蛋白D1启动子，这是β-连环蛋白的既定靶点，但只有IRF-1被招募到核糖体DNA(RDNA)启动子。UBF蛋白(已知与IRS-1和β-连环蛋白相互作用)也可在细胞周期蛋白D1和rDNA启动子中检测到。这些结果表明，IRS-1(由IGF-1受体激活)是调节β-连环蛋白亚细胞定位和活性的几种蛋白质之一。IRS-1能够定位于RNA聚合酶II(带有β-连环蛋白)和RNA聚合酶I调节的启动子，这为IRS-1对细胞大小和细胞增殖的影响提供了一个解释。IRS-1的强制核定位导致β-连环素的核转位和正常小鼠胚胎成纤维细胞的转化(软琼脂中的集落形成)支持了这种可能性。
Previous work has shown that the transcriptional regulator beta-catenin can translocate to the nuclei when cells are stimulated with the type 1 insulin-like growth factor (IGF-1). We show by immunocoprecipitation and by confocal microscopy that beta-catenin binds to and co-localizes with the insulin receptor substrate-1 (IRS-1), a docking protein for both the insulin and the IGF-1 receptors. IRS-1 is required for IGF-1-mediated nuclear translocation of beta-catenin, resulting in the activation of the beta-catenin target genes. IGF-1-mediated nuclear translocation of beta-catenin is facilitated by the nuclear translocation of IRS-1. Both IRS-1 and beta-catenin are recruited to the cyclin D1 promoter, an established target for beta-catenin, but only IRF-1 is recruited to the ribosomal DNA ( rDNA) promoter. UBF proteins ( known to interact with both IRS-1 and beta-catenin) are also detectable in the cyclin D1 and rDNA promoters. These results indicate that IRS-1 ( activated by the IGF-1 receptor) is one of several proteins that regulate the subcellular localization and activity of beta-catenin. The ability of IRS-1 to localize to both RNA polymerase II ( with beta-catenin) and RNA polymerase I-regulated promoters suggest an explanation for the effect of IRS-1 on both cell growth in size and cell proliferation. This possibility is supported by the demonstration that enforced nuclear localization of IRS-1 causes nuclear translocation of beta-catenin and transformation of normal mouse embryo fibroblasts ( colony formation in soft agar).