OVEREXPRESSION & ACTIVATION OF INSULIN RECEPTOR AND DNA REPAIR GENE EXPRESSION

受体对DNA修复基因的调控知之甚少， 酪氨酸激酶 ERCC 1和XPD mRNA水平的刺激是 在表达大量胰岛素受体的CHO细胞中观察到 （HIRc）、IGF-1或表皮生长因子，但在CHO细胞中不存在 过度表达激酶缺陷型胰岛素受体突变体。 这样的 反应不能归因于这些细胞周期依赖性表达 两个DNA修复基因 在胰岛素存在下孵育24小时的细胞 显示ERCC 1和XPD的稳态水平显著增加， mRNA与不存在胰岛素的情况下孵育的细胞相比。 这 胰岛素的作用主要发生在转录水平， 这些mRNA的不稳定性。 此外，抑制 放线菌酮的蛋白质合成诱导了这些蛋白质的显著衰减， 在胰岛素处理的细胞中的mRNA，这表明， 编码ERCC 1和XPD分子的信使根据不同的基因而不同。 胰岛素受体激活状态。 ERCC 1和XPD水平较高 CHO/HIRc细胞中的mRNA表达与增强的 紫外线照射后细胞存活率沿着显著降低， 程序性细胞死亡 可以得出结论，（1）过度表达 受体连接的酪氨酸激酶增加ERCC 1和XPD的量 （2）胰岛素诱导的这些mRNA水平的增加可以 至少部分地由转录事件来解释，以及（3） 胰岛素作为DNA修复基因调节剂具有重要作用 表达和功能。

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.