OVEREXPRESSION & ACTIVATION OF INSULIN RECEPTOR AND DNA REPAIR GENE EXPRESSION

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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.