OVEREXPRESSION & ACTIVATION OF INSULIN RECEPTOR AND DNA REPAIR GENE EXPRESSION

关于受体对DNA修复基因的调节知之甚少 酪氨酸激酶。刺激ERCC1和XPD基因的表达 在表达大量胰岛素受体的CHO细胞中观察 (HIRc)、IGF-1或表皮生长因子，但不在CHO细胞中 过表达激酶缺陷型胰岛素受体突变体。这样的一个 这些反应不能归因于细胞周期依赖的表达 两个DNA修复基因。细胞在胰岛素存在下孵育24小时 显示ERCC1和XPD的稳态水平显著增加 与在没有胰岛素的情况下孵育的细胞进行比较。这 胰岛素的作用主要发生在转录水平，通过一种 伴随而来的这些mRNAs的不稳定。此外，抑制 由放线菌亚胺合成的蛋白质导致这些蛋白质的显著衰退。 胰岛素处理细胞中的mRNAs，表明细胞的周转率 编码ERCC1和XPD分子的信使因 胰岛素受体的激活状态。更高水平的ERCC1和XPD CHO/HIRc细胞中的mRNA表达与 紫外线照射后细胞存活，同时显著减少 程序性细胞死亡。可以得出这样的结论：(1)过度表达 受体连接的酪氨酸激酶增加ERCC1和XPD的数量 MRNAs，(2)胰岛素诱导的这些mRNAs水平的增加可以 至少部分是由转录事件和(3) 胰岛素作为DNA修复基因的调节因子具有重要作用 表情和功能。

Little is known about the regulation of DNA repair genes by receptor tyrosine kinases. Stimulation of ERCC1 and XPD mRNA levels was observed in CHO cells expressing large numbers of receptors for insulin (HIRc), IGF-1 or epidermal growth factor, but not in CHO cells overexpressing kinase-deficient insulin receptor mutants. Such a response cannot be ascribed to cell cycle-dependent expression of these two DNA repair genes. Cells incubated for 24 h in the presence of insulin showed a significant increase in the steady-state levels of ERCC1 and XPD mRNAs compared with cells incubated in the absence of insulin. This effect of insulin takes place primarily at the transcriptional level with a concomitant destabilization of these mRNAs. Moreover, inhibition of protein synthesis by cycloheximide induced a marked decay of these mRNAs in insulin-treated cells, suggesting that the turnover rates of the messengers coding for ERCC1 and XPD molecules vary according to the state of insulin receptor activation. Higher levels of ERCC1 and XPD mRNA expression in CHO/HIRc cells was associated with an enhanced cellular survival after UV irradiation along with a dramatic reduction in programmed cell death. It can be concluded that (1) overexpression of receptor-linked tyrosine kinases increases the amount of ERCC1 and XPD mRNAs, (2) the insulin-induced increase in the levels of these mRNAs can be accounted for, at least in part, by transcriptional events and (3) insulin can have a major effect as a regulator of DNA repair gene expression and function.