title: A Peroxidase Peroxiredoxin 1-Specific Redox Regulation of the Novel FOXO3 microRNA Target let-7.
abstract: Precision in redox signaling is attained through posttranslational protein modifications such as oxidation of protein thiols. The peroxidase peroxiredoxin 1 (PRDX1) regulates signal transduction through changes in thiol oxidation of its cysteines. We demonstrate here that PRDX1 is a binding partner for the tumor suppressive transcription factor FOXO3 that directly regulates the FOXO3 stress response. Heightened oxidative stress evokes formation of disulfide-bound heterotrimers linking dimeric PRDX1 to monomeric FOXO3. Absence of PRDX1 enhances FOXO3 nuclear localization and transcription that are dependent on the presence of Cys31 or Cys150 within FOXO3. Notably, FOXO3-T32 phosphorylation is constitutively enhanced in these mutants, but nuclear translocation of mutant FOXO3 is restored with PI3K inhibition. Here we show that on H2O2exposure, transcription of tumor suppressive miRNAs let-7b and let-7c is regulated by FOXO3 or PRDX1 expression levels and that let-7c is a novel target for FOXO3. Conjointly, inhibition of let-7 microRNAs increases let-7-phenotypes in PRDX1-deficient breast cancer cells. Altogether, these data ascertain the existence of an H2O2-sensitive PRDX1-FOXO3 signaling axis that fine tunes FOXO3 activity toward the transcription of gene targets in response to oxidative stress. Antioxid. Redox Signal. 28, 62-77.
authors.affiliation: 1 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh , Pittsburgh, Pennsylvania.|2 Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute , Pittsburgh, Pennsylvania.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Hopkins
authors.affiliation: 3 Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center , Boston, Massachusetts.
authors.forename: Monica
authors.initials: M
authors.lastname: Nadler
authors.affiliation: 2 Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute , Pittsburgh, Pennsylvania.
authors.forename: John J
authors.initials: JJ
authors.lastname: Skoko
authors.affiliation: 3 Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center , Boston, Massachusetts.
authors.forename: Thierry
authors.initials: T
authors.lastname: Bertomeu
authors.affiliation: 4 Oncogenomic and Epigenetic Unit, Department of Research, Advanced Diagnostics and Technological Innovation, Translational Research Area Regina Elena National Cancer Institute , Rome, Italy .
authors.forename: Andrea
authors.initials: A
authors.lastname: Pelosi
authors.affiliation: 2 Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute , Pittsburgh, Pennsylvania.
authors.forename: Parisa Mousavi
authors.initials: PM
authors.lastname: Shafaei
authors.affiliation: 2 Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute , Pittsburgh, Pennsylvania.
authors.forename: Kevin
authors.initials: K
authors.lastname: Levine
authors.affiliation: 2 Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute , Pittsburgh, Pennsylvania.
authors.forename: Anja
authors.initials: A
authors.lastname: Schempf
authors.affiliation: 3 Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center , Boston, Massachusetts.
authors.forename: Bodvael
authors.initials: B
authors.lastname: Pennarun
authors.affiliation: 5 Department of Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: 3 Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center , Boston, Massachusetts.
authors.forename: Dipak
authors.initials: D
authors.lastname: Datta
authors.affiliation: 3 Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center , Boston, Massachusetts.|6 Institute of Biochemistry of the Romanian Academy, Bucharest, Romania .
authors.forename: Octavian
authors.initials: O
authors.lastname: Bucur
authors.affiliation: 3 Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center , Boston, Massachusetts.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ndebele
authors.affiliation: 2 Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute , Pittsburgh, Pennsylvania.
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.affiliation: 5 Department of Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania.
authors.forename: Da
authors.initials: D
authors.lastname: Yang
authors.affiliation: 4 Oncogenomic and Epigenetic Unit, Department of Research, Advanced Diagnostics and Technological Innovation, Translational Research Area Regina Elena National Cancer Institute , Rome, Italy .
authors.forename: Maria
authors.initials: M
authors.lastname: Giulia Rizzo
authors.affiliation: 3 Department of Pathology, Harvard Medical School and Beth Israel Deaconess Medical Center , Boston, Massachusetts.
authors.forename: Roya
authors.initials: R
authors.lastname: Khosravi-Far
authors.affiliation: 2 Department of Pharmacology and Chemical Biology, Magee Womens Research Institute, University of Pittsburgh Cancer Institute , Pittsburgh, Pennsylvania.
authors.forename: Carola A
authors.initials: CA
authors.lastname: Neumann
mesh_terms: D001665:Binding Sites; D002460:Cell Line; D002465:Cell Movement; D004220:Disulfides; D000071316:Forkhead Box Protein O3 / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D034622:RNA Interference
chemical_list: D004220:Disulfides; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D035683:MicroRNAs; C487931:mirnlet7 microRNA, human; C515940:PRDX1 protein, human; D054464:Peroxiredoxins
keywords: FOXO3; PRDX1; breast cancer; let-7; oxidative stress; tumor suppressor