TY - JOUR
T1 - Nrf2 amplifies oxidative stress via induction of Klf9
AU - Zucker, Shoshanna N.
AU - Fink, Emily E.
AU - Bagati, Archis
AU - Mannava, Sudha
AU - Bianchi-Smiraglia, Anna
AU - Bogner, Paul N.
AU - Wawrzyniak, Joseph A.
AU - Foley, Colleen
AU - Leonova, Katerina I.
AU - Grimm, Melissa J.
AU - Moparthy, Kalyana
AU - Ionov, Yurij
AU - Wang, Jianmin
AU - Liu, Song
AU - Sexton, Sandra
AU - Kandel, Eugene S.
AU - Bakin, Andrei V.
AU - Zhang, Yuesheng
AU - Kaminski, Naftali
AU - Segal, Brahm H.
AU - Nikiforov, Mikhail A.
PY - 2014/3/20
Y1 - 2014/3/20
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84896396136
U2 - 10.1016/j.molcel.2014.01.033
DO - 10.1016/j.molcel.2014.01.033
M3 - Article
C2 - 24613345
AN - SCOPUS:84896396136
SN - 1097-2765
VL - 53
SP - 916
EP - 928
JO - Molecular Cell
JF - Molecular Cell
IS - 6
ER -