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-nitroquinoline 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 dominant negative IGF-IRs were not rescued from 4-NQO UV-mimetic treatment. DNA 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 overcome the cell cycle arrest, observed after 4-NQO treatment, thereby enhancing the ability of NWTb3 cells to enter S phase. Interestingly, the p38 mitogen-activated protein kinase pathway was shown to represent the main signaling pathway involved in the IGF-IR-mediated rescue of UV-like damaged cells. The ability of the IGF-IR to induce DNA repair was also demonstrated by infecting NWTb3 cells with UV-irradiated adenovirus. Activation of the IGF-IR resulted in enhanced beta-galactosidase reporter gene activity demonstrating repair of the damaged DNA. This study indicates a direct role of the IGF system in the rescue of damaged cells via DNA repair.
Section on Cellular and Molecular Physiology, Clinical Endocrinology Branch, NIDDK and Gene Therapy and Therapeutics Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892-1758, USA.
L
L
Héron-Milhavet
M
M
Karas
C M
CM
Goldsmith
B J
BJ
Baum
D
D
LeRoith
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D004249:DNA Damage / Q000528:radiation effects; D004260:DNA Repair; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology / Q000528:radiation effects; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
D017526:Receptor, IGF Type 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases