Nrf2 Is a Direct PERK Substrate and Effector of PERK-Dependent Cell Survival
Top Cited Papers
Open Access
- 1 October 2003
- journal article
- research article
- Published by Taylor & Francis in Molecular and Cellular Biology
- Vol. 23 (20) , 7198-7209
- https://doi.org/10.1128/mcb.23.20.7198-7209.2003
Abstract
Activation of PERK following the accumulation of unfolded proteins in the endoplasmic reticulum (ER) promotes translation inhibition and cell cycle arrest. PERK function is essential for cell survival following exposure of cells to ER stress, but the mechanisms whereby PERK signaling promotes cell survival are not thoroughly understood. We have identified the Nrf2 transcription factor as a novel PERK substrate. In unstressed cells, Nrf2 is maintained in the cytoplasm via association with Keap1. PERK-dependent phosphorylation triggers dissociation of Nrf2/Keap1 complexes and inhibits reassociation of Nrf2/Keap1 complexes in vitro. Activation of PERK via agents that trigger the unfolded protein response is both necessary and sufficient for dissociation of cytoplasmic Nrf2/Keap1 and subsequent Nrf2 nuclear import. Finally, we demonstrate that cells harboring a targeted deletion of Nrf2 exhibit increased cell death relative to wild-type counterparts following exposure to ER stress. Our data demonstrate that Nrf2 is a critical effector of PERK-mediated cell survival.Keywords
This publication has 50 references indexed in Scilit:
- An Integrated Stress Response Regulates Amino Acid Metabolism and Resistance to Oxidative StressPublished by Elsevier ,2003
- The Keap1 BTB/POZ Dimerization Function Is Required to Sequester Nrf2 in CytoplasmJournal of Biological Chemistry, 2002
- Translation Mediated by the Internal Ribosome Entry Site of the cat-1 mRNA Is Regulated by Glucose Availability in a PERK Kinase-dependent MannerJournal of Biological Chemistry, 2002
- Cobalt Induces Heme Oxygenase-1 Expression by a Hypoxia-inducible Factor-independent Mechanism in Chinese Hamster Ovary CellsJournal of Biological Chemistry, 2001
- Diabetes Mellitus and Exocrine Pancreatic Dysfunction in Perk−/− Mice Reveals a Role for Translational Control in Secretory Cell SurvivalPublished by Elsevier ,2001
- Identification of Activating Transcription Factor 4 (ATF4) as an Nrf2-interacting ProteinJournal of Biological Chemistry, 2001
- Inhibition of ERK and p38 MAP Kinases Inhibits Binding of Nrf2 and Induction of GCS GenesBiochemical and Biophysical Research Communications, 2000
- Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2α kinaseEuropean Journal of Biochemistry, 1999
- The Glut athione S-Transferase Supergene Family: Regulation of GST and the Contribution of the lsoenzymes to Cancer Chemoprotection and Drug Resistance Part IICritical Reviews in Biochemistry and Molecular Biology, 1995
- The Glut athione S-Transferase Supergene Family: Regulation of GST and the Contribution of the lsoenzymes to Cancer Chemoprotection and Drug Resistance Part ICritical Reviews in Biochemistry and Molecular Biology, 1995