title: Increased nuclear factor-erythroid 2 p45-related factor 2 activity protects SH-SY5Y cells against oxidative damage.
abstract: The ability of cells to control the balance between the generation and quenching of reactive oxygen species is important in combating potentially damaging effects of oxidative stress. One mechanism that cells use to maintain redox homeostasis is the antioxidant response pathway. Antioxidant response elements (AREs) are cis-acting elements located in regulatory regions of antioxidant and phase II detoxification genes. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is a member of the Cap 'n' Collar family of transcription factors that binds to the ARE and regulates the transcription of specific ARE-containing genes such as NAD(P)H:quinone oxidoreductase 1, glutamylcysteine synthetase and heme oxygenase. Activation of Nrf2 results in release from its negative repressor, Kelch-like ECH-associated protein 1 (Keap1), and allows Nrf2 to translocate into the nucleus to induce gene expression. In this study, we demonstrate that increasing Nrf2 activity by various methods, including chemical induction, Nrf2 overexpression or Keap1 siRNA knockdown, protects cells against specific types of oxidative damage. Cells were protected against 6-hydroxydopamine- and 3-morpholinosydnonimine-mediated toxicity but not against 1-methyl-1-4-phenylpyridinium toxicity. As oxidative stress is a hallmark of several neurodegenerative disorders, including Parkinson's disease, pharmacological agents that selectively target the Keap1-Nrf2 pathway may provide a novel neuroprotective strategy for the treatment of these diseases.
authors.affiliation: Merck Research Laboratories, West Point, Pennsylvania, USA. tracy_cao@merck.com
authors.forename: Tracy T
authors.initials: TT
authors.lastname: Cao
authors.forename: Lei
authors.initials: L
authors.lastname: Ma
authors.forename: Geeta
authors.initials: G
authors.lastname: Kandpal
authors.forename: Lee
authors.initials: L
authors.lastname: Warren
authors.forename: J Fred
authors.initials: JF
authors.lastname: Hess
authors.forename: Guy R
authors.initials: GR
authors.lastname: Seabrook
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors / Q000633:toxicity; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000502:physiology*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D008156:Luciferases / Q000378:metabolism; D008981:Molsidomine / Q000031:analogs & derivatives / Q000633:toxicity; D051267:NF-E2-Related Factor 2; D018384:Oxidative Stress / Q000502:physiology*; D016627:Oxidopamine / Q000037:antagonists & inhibitors / Q000633:toxicity; D010957:Plasmids / Q000235:genetics; D011506:Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D006873:Hydroquinones; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011506:Proteins; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D015534:Trans-Activators; C002385:linsidomine; D016627:Oxidopamine; C018855:2-tert-butylhydroquinone; D008981:Molsidomine; D008156:Luciferases; D015655:1-Methyl-4-phenylpyridinium