Insulin-like growth factor-I (IGF-I) receptor activation rescues UV-damaged cells through a p38 signaling pathway - Potential role of the IGF-I receptor in DNA repair

The activated insulin-like growth factor-I receptor (IGF-IR) is implicated in mitogenesis, transformation, and anti-apoptosis. To investigate the role of the IGF-IR in protection from UV-mimetic-induced DNA damage, 4-nitroqui noline N-oxide (4-NQO) was used. In this study we show that the activation of the IGF-IR is capable of rescuing NWTb3 cells overexpressing normal IGF- IRs from 4-NQO-induced DNA damage as demonstrated by cellular proliferation assays, This action was specific for the IGF-IR since cells expressing dom inant negative IGF-IRs were not rescued from 4-NQO UV-mimetic treatment. DN A damage induced by 4-NQO in NWTb3 cells was significantly decreased after IGF-IR activation as measured by comet assay, IGF-I was also able to overco me the cell cycle arrest, observed after 4-NQO treatment, thereby enhancing the ability of NWTb3 cells to enter S phase. Interestingly, the p38 mitoge n-activated protein kinase pathway was shown to represent the main signalin g pathway involved in the TGF-IR-mediated rescue of UV-like damaged cells. The ability of the IGF-IR to induce DNA repair was also demonstrated by inf ecting NWTb3 cells with W-irradiated adenovirus, Activation of the IGF-IR r esulted in enhanced P-galactosidase reporter gene activity demonstrating re pair of the damaged DNA, This study indicates a direct role of the IGF syst em in the rescue of damaged cells via DNA repair.