title: Insulin-like growth factor-1-mediated AKT activation postpones the onset of ultraviolet B-induced apoptosis, providing more time for cyclobutane thymine dimer removal in primary human keratinocytes.
abstract: Insulin-like growth factor-1 (IGF-1) acts as a potent survival factor in numerous cell lines, primarily through activation of the AKT signaling pathway. Although some targets of this pathway have known anti-apoptotic functions, its relationship with the improved survival of cells after exposure to environmental stresses, including UVB, remains largely unclear. We report that in growth factor-deprived keratinocytes, IGF-1 significantly and consistently delayed the onset of UVB-induced apoptosis by >7 h. This delay allowed IGF-1-supplemented keratinocytes to repair significantly more cyclobutane thymine dimers than their growth factor-deprived counterparts. This increase in cyclobutane thymine removal resulted in enhanced survival if the amount of DNA damage was not too high. To increase cell survival after UVB irradiation, IGF-1 supplementation was required only during this initial time period in which extra repair was executed. Finally, we show that IGF-1 mediated this delay in the onset of UVB-induced apoptosis through activation of the AKT signaling pathway. We therefore believe that the AKT signaling pathway increases cell survival after a genotoxic insult such as UVB irradiation not by inhibiting the apoptotic stimulus, but only by postponing the induction of apoptosis, giving the DNA repair mechanism more time to work.
authors.affiliation: Department of Dermatology, Faculty of Medicine, Katholieke Universiteit, B-3000 Leuven, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Decraene
authors.forename: Patrizia
authors.initials: P
authors.lastname: Agostinis
authors.forename: Roger
authors.initials: R
authors.lastname: Bouillon
authors.forename: Hugo
authors.initials: H
authors.lastname: Degreef
authors.forename: Marjan
authors.initials: M
authors.lastname: Garmyn
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D017209:Apoptosis; D015139:Blotting, Southern; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D004396:Coloring Agents / Q000494:pharmacology; D004249:DNA Damage; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D015603:Keratinocytes / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011740:Pyrimidine Dimers / Q000378:metabolism*; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013941:Thymine / Q000378:metabolism; D013997:Time Factors; D014466:Ultraviolet Rays
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D004396:Coloring Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011740:Pyrimidine Dimers; D013778:Tetrazolium Salts; D013844:Thiazoles; D013941:Thymine; C494918:AKT1 protein, human; C022616:thiazolyl blue; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole