title: Mutation of ATF4 mediates resistance of neuronal cell lines against oxidative stress by inducing xCT expression.
abstract: Selecting neuronal cell lines for resistance against oxidative stress might recapitulate some adaptive processes in neurodegenerative diseases where oxidative stress is involved like Parkinson's disease. We recently reported that in hippocampal HT22 cells selected for resistance against oxidative glutamate toxicity, the cystine/glutamate antiporter system x(c)(-), which imports cystine for synthesis of the antioxidant glutathione, and its specific subunit, xCT, are upregulated. (Lewerenz et al., J Neurochem 98(3):916-25). Here, we show that in these glutamate-resistant HT22 cells upregulation of xCT mediates glutamate resistance, and xCT expression is induced by upregulation of the transcription factor ATF4. The mechanism of ATF4 upregulation consists of a 13 bp deletion in the upstream open reading frame (uORF2) overlapping the ATF4 open reading frame. The resulting uORF2-ATF4 fusion protein is efficiently translated even at a low phosphorylation levels of the translation initiation factor eIF2α, a condition under which ATF4 translation is normally suppressed. A similar ATF4 mutation associated with prominent upregulation of xCT expression was identified in PC12 cells selected for resistance against amyloid β-peptide. Our data indicate that ATF4 has a central role in regulating xCT expression and resistance against oxidative stress. ATF4 mutations might have broader significance as upregulation of xCT is found in tumor cells and associated with anticancer drug resistance.
authors.affiliation: Department of Neurology, University of Ulm, Ulm, Germany. jan.lewerenz@googlemail.com
authors.forename: J
authors.initials: J
authors.lastname: Lewerenz
authors.forename: H
authors.initials: H
authors.lastname: Sato
authors.forename: P
authors.initials: P
authors.lastname: Albrecht
authors.forename: N
authors.initials: N
authors.lastname: Henke
authors.forename: R
authors.initials: R
authors.lastname: Noack
authors.forename: A
authors.initials: A
authors.lastname: Methner
authors.forename: P
authors.initials: P
authors.lastname: Maher
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics* / Q000378:metabolism*; D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D026922:Amino Acid Transport Systems, Acidic; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D005978:Glutathione; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051701:Activating Transcription Factor 4; D027182:Amino Acid Transport System y+; D026922:Amino Acid Transport Systems, Acidic; D005978:Glutathione; C081452:Atf4 protein, mouse; C497110:Atf4 protein, rat; C492255:Slc7a11 protein, mouse; C000723960:Slc7a11 protein, rat
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