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首页> 外文期刊>Archives of Toxicology >Driving gradual endogenous c-myc overexpression by flow-sorting: intracellular signaling and tumor cell phenotype correlate with oncogene expression
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Driving gradual endogenous c-myc overexpression by flow-sorting: intracellular signaling and tumor cell phenotype correlate with oncogene expression

机译：通过分流驱动逐渐的内源性c-myc过表达：细胞内信号传导和肿瘤细胞表型与癌基因表达相关

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Insulin-exposed rat mammary cancer cells were flow sorted based on a c-myc reporter plasmid encoding a destabilized green fluorescent protein. Sorted cells exhibited gradual increases in c-myc levels. Cells overexpressing c-myc by only 10% exhibited phenotypic changes attributable to c-myc overexpression, such as cell cycle disturbances, increased cell size, and overexpression of the S6 ribosomal protein. Cells overexpressing c-myc by 70% exhibited additional phenotypic changes typical of c-myc overexpression, such as increased histone H3 phosphorylation, and reduced adherence. Sorted cells also exhibited overexpression of the IGF-1R, and slightly elevated expression of the IR. Increased susceptibility to the mitogenic effect of insulin was seen in a small proportion of the sorted cells, and insulin was more effective in activating the p44/42 MAPK pathway, but not the PI3K pathway, in the sorted cells than in the nonsorted cell population. To our knowledge, this is the first in vitro system allowing functional coupling between mitogenic signaling by a well-defined growth factor and gradual overexpression of the normal, endogenous c-myc gene. Thus, our flow-sorting approach provides an alternative modeling of the receptor-mediated carcinogenic process, compared to the currently used approaches of recombinant constitutive or conditional overexpression of oncogenic transmembrane receptor tyrosine kinases or oncogenic transcription factors.
机译：根据编码不稳定的绿色荧光蛋白的c-myc报告质粒，对胰岛素暴​​露的大鼠乳腺癌细胞进行流分选。分选的细胞表现出c-myc水平的逐渐增加。过表达c-myc仅10％的细胞表现出可归因于c-myc过表达的表型变化，例如细胞周期紊乱，细胞大小增加和S6核糖体蛋白过表达。过度表达c-myc 70％的细胞表现出c-myc过表达典型的其他表型变化，例如组蛋白H3磷酸化增加和粘附减少。分选的细胞还表现出IGF-1R的过表达，并且IR的表达略微升高。在少数分选的细胞中发现胰岛素对促有丝分裂作用的敏感性增加，并且与未分选的细胞群相比，在分选的细胞中胰岛素在激活p44 / 42 MAPK途径而非PI3K途径方面更有效。据我们所知，这是第一个体外系统，其允许通过明确定义的生长因子进行促有丝分裂信号传递与正常内源性c-myc基因逐渐过度表达之间的功能偶联。因此，与目前使用的重组组成型或条件性过表达致癌跨膜受体酪氨酸激酶或致癌转录因子的方法相比，我们的分流方法提供了一种受体介导的致癌过程的替代模型。

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