Role of glutaredoxin in metabolic oxidative stress. Glutaredoxin as a sensor of oxidative stress mediated by H2O2

Jae J Song; Juong G Rhee; Mohan Suntharalingam; Susan A Walsh; Douglas R Spitz; Yong J Lee

doi:10.1074/jbc.M206826200

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Role of glutaredoxin in metabolic oxidative stress. Glutaredoxin as a sensor of oxidative stress mediated by H2O2

Journal article

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Peer reviewed

Role of glutaredoxin in metabolic oxidative stress. Glutaredoxin as a sensor of oxidative stress mediated by H2O2

Jae J Song, Juong G Rhee, Mohan Suntharalingam, Susan A Walsh, Douglas R Spitz and Yong J Lee

The Journal of biological chemistry, Vol.277(48), pp.46566-46575

11/29/2002

DOI: 10.1074/jbc.M206826200

PMID: 12244106

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Abstract

Epitope-tagged glutaredoxin (GRX) was utilized to determine the role of GRX in oxidative stress-induced signaling and cytotoxicity in glucose-deprived human cancer cells (MCF-7/ADR and DU-145). GRX-overexpressing cells demonstrated resistance to glucose deprivation-induced cytotoxicity and decreased activation of c-Jun N-terminal kinase (JNK1). Deletion mutants showed the C-terminal portion of apoptosis signal-regulating kinase 1 (ASK1) bound GRX, and glucose deprivation disrupted binding. Treatment with l-buthionine-(S,R)-sulfoximine reduced glutathione content by 99% and prevented glucose deprivation-induced dissociation of GRX from ASK1. A thiol antioxidant, N-acetyl-l-cysteine, or overexpression of an H(2)O(2) scavenger, catalase, inhibited glucose deprivation-induced dissociation of GRX from ASK1. GRX active site cysteine residues (Cys(22) and Cys(25)) were required for dissociation of GRX from ASK1 during glucose deprivation. Kinase assays revealed that SEK1 and JNK1 were regulated in an ASK1-dependent fashion during glucose deprivation. Overexpression of GRX or catalase inhibited activation of ASK1-SEK1-JNK1 signaling during glucose deprivation. These results demonstrate that GRX is a negative regulator of ASK1 and dissociation of GRX from ASK1 activates ASK1-SEK1-JNK1 signaling leading to cytotoxicity during glucose deprivation. These results support the hypothesis that the GRX-ASK1 interaction is redox sensitive and regulated in a glutathione-dependent fashion by H(2)O(2).

Acetylcysteine - pharmacology

Base Sequence

DNA Primers

Glucose - metabolism

Glutaredoxins

Humans

Hydrogen Peroxide - pharmacology

MAP Kinase Signaling System

Models, Theoretical

Oxidative Stress - physiology

Oxidoreductases

Proteins - genetics

Proteins - physiology

Signal Transduction - physiology

Tumor Cells, Cultured

Details

Title: Subtitle: Role of glutaredoxin in metabolic oxidative stress. Glutaredoxin as a sensor of oxidative stress mediated by H2O2
Creators: Jae J Song - University of Pittsburgh
Juong G Rhee - University of Maryland, Baltimore
Mohan Suntharalingam - University of Maryland, Baltimore
Susan A Walsh - University of Iowa
Douglas R Spitz - University of Iowa
Yong J Lee - University of Pittsburgh Cancer Institute
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.277(48), pp.46566-46575
DOI: 10.1074/jbc.M206826200
PMID: 12244106
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Grant note: CA48000 / NCI NIH HHS CA66081 / NCI NIH HHS HL51469 / NHLBI NIH HHS
Language: English
Date published: 11/29/2002
Academic Unit: Radiology; Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center
Record Identifier: 9984312968802771

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