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.
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.
Decraene
David
D
Department of Dermatology, Faculty of Medicine, Katholieke Universiteit, B-3000 Leuven, Belgium.
Agostinis
Patrizia
P
Bouillon
Roger
R
Degreef
Hugo
H
Garmyn
Marjan
M
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
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