title: Nrf2 amplifies oxidative stress via induction of Klf9.
abstract: Reactive oxygen species (ROS) activate NF-E2-related transcription factor 2 (Nrf2), a key transcriptional regulator driving antioxidant gene expression and protection from oxidant injury. Here, we report that in response to elevation of intracellular ROS above a critical threshold, Nrf2 stimulates expression of transcription Kruppel-like factor 9 (Klf9), resulting in further Klf9-dependent increases in ROS and subsequent cell death. We demonstrated that Klf9 independently causes increased ROS levels in various types of cultured cells and in mouse tissues and is required for pathogenesis of bleomycin-induced pulmonary fibrosis in mice. Mechanistically, Klf9 binds to the promoters and alters the expression of several genes involved in the metabolism of ROS, including suppression of thioredoxin reductase 2, an enzyme participating in ROS clearance. Our data reveal an Nrf2-dependent feedforward regulation of ROS and identify Klf9 as a ubiquitous regulator of oxidative stress and lung injury.
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Shoshanna N
authors.initials: SN
authors.lastname: Zucker
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Emily E
authors.initials: EE
authors.lastname: Fink
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Archis
authors.initials: A
authors.lastname: Bagati
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Sudha
authors.initials: S
authors.lastname: Mannava
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Bianchi-Smiraglia
authors.affiliation: Department of Pathology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Bogner
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Wawrzyniak
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Foley
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Katerina I
authors.initials: KI
authors.lastname: Leonova
authors.affiliation: Department of Medicine Immunology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Grimm
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Kalyana
authors.initials: K
authors.lastname: Moparthy
authors.affiliation: Department of Cancer Genetics, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Yurij
authors.initials: Y
authors.lastname: Ionov
authors.affiliation: Department of Biostatistics and Bioinformatics, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biostatistics and Bioinformatics, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Laboratory Animal Resources, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Sexton
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Eugene S
authors.initials: ES
authors.lastname: Kandel
authors.affiliation: Department of Cancer Genetics, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Bakin
authors.affiliation: Department of Cancer Prevention and Control, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Yuesheng
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Roswell Park Cancer Institute, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.affiliation: Department of Medicine Immunology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
authors.affiliation: Department of Cell Stress Biology, Buffalo, New York, 14263, USA, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520 USA.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Nikiforov
mesh_terms: D000818:Animals; D001665:Binding Sites; D001761:Bleomycin; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D041681:NIH 3T3 Cells; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species; D015398:Signal Transduction
chemical_list: C489676:KLF9 protein, human; C489675:Klf9 protein, mouse; D051741:Kruppel-Like Transcription Factors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D001761:Bleomycin; D008156:Luciferases