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PMID: 7796817 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Rapid responses to oxidative stress mediated by iron regulatory protein.

The EMBO journal ·Vol. 14 ·No. 12 ·1995-06-15 ·Pages 2917-24

Pantopoulos K, Hentze MW

Abstract

Reactive oxygen intermediates (ROIs), including superoxide anion (O2.-) and hydrogen peroxide (H2O2), are by-products of aerobic metabolism with potential toxicity towards cellular macromolecules, including lipids, proteins and DNA. Excess ROIs, a condition referred to as oxidative stress, is considered to be a major contributor to ageing, degenerative diseases and reperfusion injury. The reactivity of H2O2 with iron (Fenton reaction) intimately connects oxidative stress and cellular iron metabolism. We have found a novel oxidative stress response pathway in mammalian cells which links oxidative stress to the regulation of iron metabolism. Exposure of cells to H2O2 leads to reduced synthesis of the intracellular iron storage protein ferritin and stimulates transferrin receptor (TfR) mRNA expression. Both responses are post-transcriptional and result from induction of iron regulatory protein (IRP) binding to iron-responsive elements (IREs) in ferritin and TfR mRNAs. IRP induction by H2O2 appears to involve the disassembly of its cubane 4Fe-4S cluster and occurs even in the presence of the protein synthesis inhibitor cycloheximide. The induction kinetics by H2O2 far exceed those by iron starvation. The response requires cellular integrity and cannot be elicited in cell extracts. Whereas the activation of IRP by iron depletion is insensitive to okadaic acid, the rapid induction by H2O2 is blocked by this inhibitor of type I/IIa protein phosphatases. Thus okadaic acid separates the activation pathways by iron depletion and oxidative stress, suggesting the involvement of stress-induced kinase/phosphatase pathways in the latter.

MeSH Terms
Aconitate Hydratase/metabolism Animals Arginine/pharmacology Cells, Cultured Citrates/metabolism Citric Acid Ethers, Cyclic/pharmacology Ferritins/biosynthesis Fibroblasts/metabolism Heme/pharmacology Hydrogen Peroxide/pharmacology Iron-Regulatory Proteins Mice Okadaic Acid Oxidative Stress/drug effects,physiology Phosphoprotein Phosphatases/antagonists & inhibitors RNA, Messenger/biosynthesis,metabolism RNA-Binding Proteins/metabolism Receptors, Transferrin/biosynthesis
Chemicals
Citrates Ethers, Cyclic Iron-Regulatory Proteins RNA, Messenger RNA-Binding Proteins Receptors, Transferrin Okadaic Acid Citric Acid Heme Ferritins Arginine Hydrogen Peroxide Phosphoprotein Phosphatases Aconitate Hydratase heme arginate
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Pantopoulos K
Gene Expression Programme, European Molecular Biology Laboratory, Heidelberg, Germany.
Hentze M W
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
0261-4189
Published
1995-06-15
Pages
2917-24
Language
English
Region
England
NLM ID
8208664
PMCID
PMC398411
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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