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PMID: 14517290 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival.

Molecular and cellular biology ·Vol. 23 ·No. 20 ·2003-10-00 ·Pages 7198-209

Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA

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.

MeSH Terms
Active Transport, Cell Nucleus Animals Annexin A5/pharmacology Apoptosis Blotting, Northern Cell Cycle Cell Nucleus/metabolism Cell Survival Cytoplasm/metabolism DNA-Binding Proteins/metabolism Endoplasmic Reticulum/metabolism Genes, Reporter Glutathione Transferase/metabolism Immunoblotting Mice Microscopy, Fluorescence Models, Biological NF-E2-Related Factor 2 NIH 3T3 Cells Phosphorylation Plasmids/metabolism Precipitin Tests Protein Binding Protein Biosynthesis Protein Folding Protein Transport Signal Transduction Subcellular Fractions Time Factors Trans-Activators/metabolism Transcription, Genetic Two-Hybrid System Techniques eIF-2 Kinase/metabolism
Chemicals
Annexin A5 DNA-Binding Proteins NF-E2-Related Factor 2 Nfe2l2 protein, mouse Trans-Activators Glutathione Transferase PERK kinase eIF-2 Kinase
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Cullinan Sara B
The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, Department of Cancer Biology, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104, USA.
Zhang Donna
Hannink Mark
Arvisais Edward
Kaufman Randal J
Diehl J Alan
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.20.7198-7209.2003
Published
2003-10-00
Pages
7198-209
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC230321
Subset
IM
Grants
NIGMS NIH HHS · R01 GM059213 · United States
NIEHS NIH HHS · R21 ES011721 · United States
NIEHS NIH HHS · ES11721 · United States
NIGMS NIH HHS · GM59213 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.20.7198-7209.2003 PMC Full Text View journal details
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