Ataxia-Telangiectasia Mutated Gene Controls Insulin-Like Growth Factor I Receptor Gene Expression in a Deoxyribonucleic Acid Damage Response Pathway via Mechanisms Involving Zinc-Finger Transcription Factors Sp1 and WT1

AbstractThe IGF-I receptor (IGF-IR) has a central role in cell cycle progression as well as in the establishment of the transformed phenotype. Increased expression of the IGF-IR gene, in addition, is correlated with acquisition of radioresistance for cell killing. The ataxia-telangiectasia mutated (ATM) gene product has a pivotal role in coordinating the cellular response to DNA damage. The present study was aimed at testing the hypothesis that the ability of ATM to coordinate the DNA damage response that will lead to cell survival or, alternatively, to apoptosis depends, to a significant extent, on its capacity to control IGF-IR gene expression. The potential involvement of ATM in regulation of IGF-IR expression and function was investigated in isogenic cells with and without ATM function [AT22IJE-T/pEBS7 (ATM −/−) and ATM-corrected AT22IJE-T/YZ5 (ATM +/+) cells and 293 human embryonic kidney cells transfected with small interfering RNAs targeted to ATM]. In addition, the effect of ATM on IGF-IR expression was assessed in nonisogenic cells with ATM function (HFF + human telomerase reverse transcriptase) and without ATM function (GM5823 + human telomerase reverse transcriptase). Results obtained showed that IGF-IR gene expression and IGF-IR promoter activity were largely reduced in ATM −/− cells. Addition of the radiomimetic agent neocarzinostatin for 4 h, however, induced a significant increase in IGF-IR levels in cells without ATM function. In addition, IGF-I-induced IGF-IR and insulin receptor substrate-1 phosphorylation were greatly impaired in ATM-deficient cells. Furthermore, we identified zinc-finger transcription factors Sp1 and WT1 as potential mediators of the effect of ATM on IGF-IR gene expression. The present data suggests that the IGF-IR gene is a novel downstream target in an ATM-mediated DNA damage response pathway. Deregulated expression of the IGF-IR gene after ionizing radiation may be linked to genomic instability and enhanced transforming capacity.