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微阵列分析以及对参与胰岛素样生长因子-1受体信号传导和基因表达的新分子的鉴定。

Microarray analysis and identification of novel molecules involved in insulin-like growth factor-1 receptor signaling and gene expression.

作者信息

Dupont Joelle, Dunn Sandra E, Barrett J Carl, LeRoith Derek

机构信息

Physiologie de la Reproduction et des Comportements, Unite Mixte de Recherches 6073, Institut National de la Recherche Agronomique-Centre National de la Recherche Scientifique, Université F. Rabelais, Tours 37380 Nouzilly, France.

出版信息

Recent Prog Horm Res. 2003;58:325-42. doi: 10.1210/rp.58.1.325.

Abstract

The insulin receptor (IR) and the insulin-like growth factor-1 receptor (IGF-1R) are members of the same subfamily of receptor tyrosine kinases. The two receptors phosphorylate many of the same substrates and activate the same signaling modules, including the mitogen-activated protein kinase (MAPK) and phosphatidyl inositol 3' kinase (PI3K) signaling pathways. Although the IR and IGF-1R share some redundant functions in metabolism, cell growth, differentiation, and apoptosis, they also exhibit distinct physiological roles. Some of these may be due to differences in tissue distribution, receptor structure, formation of hybrid receptors, or mechanisms of ligand binding. However, the divergent effects of insulin and IGF-1 also may be explained by specificity in the intracellular signals generated by insulin and IGF-1. In particular, the IR and IGF-1R are capable of triggering their own biological responses by using specific or preferential substrates, molecular adapters, or signaling pathways. In a recent study, we used cDNA microarray analysis to identify genes differentially regulated by insulin and IGF-1. Mouse NIH-3T3 fibroblasts expressing either the wild-type human IGF-1R or IR were stimulated with either IGF-1 or insulin, respectively. We identified 39 genes differentially regulated by insulin and IGF-1. Most of these genes had not been reported previously to be responsive to insulin or IGF-1. The genes induced by IGF-1 generally were involved in mitogenesis or differentiation, while the genes found to be induced by insulin did not conform to any particular category. In a separate study, immortalized breast epithelial cells were stimulated with IGF-1 and a cDNA microarray analysis was used to generate a profile of IGF-1-regulated genes. A number of genes known to be involved in angiogenesis were found to be regulated by IGF-1. These results strongly suggest that this technology may be extremely useful in identifying groups of genes that are specifically regulated by different ligands and their activated receptors.

摘要

胰岛素受体(IR)和胰岛素样生长因子-1受体(IGF-1R)属于受体酪氨酸激酶同一亚家族的成员。这两种受体可使许多相同的底物磷酸化,并激活相同的信号传导模块,包括丝裂原活化蛋白激酶(MAPK)和磷脂酰肌醇3'激酶(PI3K)信号通路。尽管IR和IGF-1R在代谢、细胞生长、分化和凋亡方面具有一些冗余功能,但它们也表现出不同的生理作用。其中一些可能归因于组织分布、受体结构、杂合受体的形成或配体结合机制的差异。然而,胰岛素和IGF-1的不同作用也可能由胰岛素和IGF-1产生的细胞内信号的特异性来解释。特别是,IR和IGF-1R能够通过使用特定的或优先的底物、分子衔接蛋白或信号通路来触发它们自身的生物学反应。在最近的一项研究中,我们使用cDNA微阵列分析来鉴定受胰岛素和IGF-1差异调节的基因。分别用IGF-1或胰岛素刺激表达野生型人IGF-1R或IR的小鼠NIH-3T3成纤维细胞。我们鉴定出39个受胰岛素和IGF-1差异调节的基因。这些基因中的大多数以前尚未报道对胰岛素或IGF-1有反应。由IGF-1诱导的基因通常参与有丝分裂或分化,而发现由胰岛素诱导的基因则不符合任何特定类别。在另一项研究中,用IGF-1刺激永生化乳腺上皮细胞,并使用cDNA微阵列分析来生成IGF-1调节基因的图谱。发现许多已知参与血管生成的基因受IGF-1调节。这些结果强烈表明,这项技术在鉴定由不同配体及其活化受体特异性调节的基因组方面可能极其有用。

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