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首页> 外文期刊>Molecular and Cellular Biology >Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells.
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Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells.

机译：胰岛素受体底物1（IRS-1）和IRS-2在IRS-1缺陷细胞中的差异信号。

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Mice made insulin receptor substrate 1 (IRS-1) deficient by targeted gene knockout exhibit growth retardation and abnormal glucose metabolism due to resistance to the actions of insulin-like growth factor 1 (IGF-1) and insulin (E. Araki et al., Nature 372:186-190, 1994; H. Tamemoto et al., Nature 372:182-186, 1994). Embryonic fibroblasts and 3T3 cell lines derived from IRS-1-deficient embryos exhibit no IGF-1-stimulated IRS-1 phosphorylation or IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity but exhibit normal phosphorylation of IRS-2 and Shc and normal IRS-2-associated PI 3-kinase activity. IRS-1 deficiency results in a 70 to 80% reduction in IGF-1-stimulated cell growth and parallel decreases in IGF-1-stimulated S-phase entry, PI 3-kinase activity, and induction of the immediate-early genes c-fos and egr-1 but unaltered activation of the mitogen-activated protein kinases ERK 1 and ERK 2. Expression of IRS-1 in IRS-1-deficient cells by retroviral gene transduction restores IGF-1-stimulated mitogenesis, PI 3-kinase activation, and c-fos and egr-1 induction in proportion to the level of reconstitution. Increasing the level of IRS-2 in these cells by using a retrovirus reconstitutes IGF-1 activation of PI 3-kinase and immediate-early gene expression to the same degree as expression of IRS-1; however, IRS-2 overexpression has only a minor effect on IGF-1 stimulation of cell cycle progression. These results indicate that IRS-1 is not necessary for activation of ERK 1 and ERK 2 and that activation of ERK 1 and ERK 2 is not sufficient for IGF-1-stimulated activation of c-fos and egr-1. These data also provide evidence that IRS-1 and IRS-2 are not functionally interchangeable signaling intermediates for stimulation of mitogenesis despite their highly conserved structure and many common functions such as activating PI 3-kinase and early gene expression.
机译：由于对胰岛素样生长因子1（IGF-1）和胰岛素的抗药性，使目标基因敲除缺陷的小鼠胰岛素受体底物1（IRS-1）表现出生长迟缓和异常葡萄糖代谢（E.Araki等。 ，Nature 372：186-190，1994; H.Tamemoto等，Nature 372：182-186，1994）。源自IRS-1缺陷胚胎的胚胎成纤维细胞和3T3细胞系未显示IGF-1刺激的IRS-1磷酸化或IRS-1相关的磷脂酰肌醇3-激酶（PI 3-激酶）活性，但未显示IRS-2的正常磷酸化以及Shc和正常的IRS-2相关PI 3激酶活性。 IRS-1缺乏导致IGF-1刺激的细胞生长减少70％至80％，而IGF-1刺激的S期进入，PI 3激酶活性和速生早期基因c-的诱导平行降低fos和egr-1，但丝裂原激活的蛋白激酶ERK 1和ERK 2的激活未改变。通过逆转录病毒基因转导在IRS-1缺陷细胞中表达IRS-1，可恢复IGF-1刺激的有丝分裂，PI 3激酶激活。 ，以及c-fos和egr-1的诱导与重构水平成正比。通过使用逆转录病毒提高这些细胞中IRS-2的水平，可以重建IGF-1对PI 3激酶的激活和立即早期基因表达，使其表达程度与IRS-1相同。但是，IRS-2的过度表达对IGF-1刺激的细胞周期进程仅有很小的影响。这些结果表明，IRS-1对于激活ERK 1和ERK 2并不是必需的，而ERK 1和ERK 2的激活对于IGF-1刺激的c-fos和egr-1的激活是不够的。这些数据还提供了证据，尽管IRS-1和IRS-2具有高度保守的结构和许多常见功能（例如激活PI 3激酶和早期基因表达），但它们在刺激有丝分裂中不是功能可互换的信号传导中间体。

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