title: Compensatory activation of ERK1/2 in Atg5-deficient mouse embryo fibroblasts suppresses oxidative stress-induced cell death.
abstract: Despite of the increasing evidence that oxidative stress may induce non-apoptotic cell death or autophagic cell death, the mechanism of this process is unclear. Here, we report a role and a down-stream molecular event of Atg5 during oxidative stress-induced cell death. Compared to wild type (WT) cells, Atg5-deficient mouse embryo fibroblasts (Atg5-/- MEFs) and Atg5 knockdown HT22 neuronal cells were more resistant to cell death induced by H2O2. On the contrary, Atg5-/- MEFs were as sensitive to tumor necrosis factor (TNF)-alpha and cycloheximide as WT cells, and were more sensitive to cell death triggered by amino acid-deprivation than WT MEFs. Treatment with H2O2 induced the recruitment of a GFP-LC3 fusion protein and conversion of LC3 I to LC3 II, correlated with the extent of autophagosome formation in WT cells, but much less in Atg5-deficient cells. Among stress kinases, ERK1/2 was markedly activated in Atg5-/- MEFs and Atg5 knockdown HT22 and SH-SY5Y neuronal cells. The inhibition of ERK1/2 by MEK1 inhibitor (PD98059) or dominant negative ERK2 enhanced the susceptibility of Atg5-/- MEFs to H2O2-induced cell death. Further, reconstitution of Atg5 sensitized Atg5-/- MEFs to H2O2 and suppressed the activation of ERK1/2. These results suggest that the inhibitory effect of Atg5 deficiency on cell death is attributable by the compensatory activation of ERK1/2 in Atg5-/- MEFs during oxidative stress-induced cell death.
authors.affiliation: School of Biological Science/Bio-MAX Institute, Seoul National University, Shillim-dong, Gwanak-gu, Seoul, Korea.
authors.forename: Jong-Ok
authors.initials: JO
authors.lastname: Pyo
authors.forename: Jihoon
authors.initials: J
authors.lastname: Nah
authors.forename: Hyo-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Ho-June
authors.initials: HJ
authors.lastname: Lee
authors.forename: Jungun
authors.initials: J
authors.lastname: Heo
authors.forename: Heuiran
authors.initials: H
authors.lastname: Lee
authors.forename: Yong-Keun
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000818:Animals; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D016923:Cell Death; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D005419:Flavonoids; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D014409:Tumor Necrosis Factor-alpha; D003513:Cycloheximide; D006861:Hydrogen Peroxide; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one