Differential regulation of redox responsive transcription factors by the nephrocarcinogen 2,3,5-tris(glutathion-S-yl)hydroquinone

T. J. Weber, Q. Huang, Terrence Monks, Serrine Lau

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

2,3,5-Tris(glutathion-S-yl)hydroquinone [TGHQ] is a potent nephrotoxicant and nephrocarcinogen, and induces a spectrum of mutations in human and bacterial cells consistent with those attributed to reactive oxygen species (ROS). Studies were conducted to determine whether the oxidative stress induced by TGHQ in renal proximal tubule epithelial cells (LLC-PK1) modulates transcriptional activities widely implicated in transformation responses, namely 12-O-tetradecanoyl phorbol 13-acetate (TPA) responsive element (TRE)- and nuclear factor kappa B (NF-κB)-binding activity. TGHQ increased TRE- and NF-κB-binding activity in a concentration- and time-dependent manner. Catalase fully inhibited peak TGHQ-mediated TRE- and NF-κB-binding activity. In contrast, although deferoxamine fully inhibited TGHQ-mediated TRE-binding activity, it had only a marginal effect on NF-κB-binding activity. Collectively, these data indicate that TGHQ modulates TRE- and NF-κB-binding activity in an ROS-dependent fashion. Cycloheximide and actinomycin D fully inhibited TGHQ-mediated TRE-binding activity, but in the absence of TGHQ increased NF-κB-binding activity. Although protein kinase C (PKC) is widely implicated in stress response signaling, pretreatment of cells with PKC inhibitors (H-89, calphostin C) did not modulate TGHQ-mediated DNA-binding activities. In contrast, pretreatment of cells with (PD098059), a mitogen activated protein kinase kinase (MEK) inhibitor, markedly reduced TGHQ-mediated TRE-binding activity, but enhanced TGHQ-mediated NF-κB-binding activity. We conclude that TGHQ-mediated TRE- and NF-κB-binding activities are ROS-dependent. Although there is a common requirement for hydrogen peroxide (H2O2) in the regulation of these DNA-binding activities, there appears to be divergent regulation after H2O2 generation in renal epithelial cells.

Original languageEnglish (US)
Pages (from-to)814-821
Number of pages8
JournalChemical Research in Toxicology
Volume14
Issue number7
DOIs
StatePublished - 2001
Externally publishedYes

Fingerprint

NF-kappa B
Oxidation-Reduction
Transcription Factors
Reactive Oxygen Species
Mitogen-Activated Protein Kinase Kinases
Protein Kinase C
Epithelial Cells
Cells
Proximal Kidney Tubule
Deferoxamine
Oxidative stress
2,3,5-(triglutathion-S-yl)hydroquinone
Protein C Inhibitor
DNA
Dactinomycin
Tetradecanoylphorbol Acetate
Cycloheximide
Protein Kinase Inhibitors
Catalase
Hydrogen Peroxide

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Chemistry(all)
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

@article{e83ab10e3e04414cb45a3a707da25660,
title = "Differential regulation of redox responsive transcription factors by the nephrocarcinogen 2,3,5-tris(glutathion-S-yl)hydroquinone",
abstract = "2,3,5-Tris(glutathion-S-yl)hydroquinone [TGHQ] is a potent nephrotoxicant and nephrocarcinogen, and induces a spectrum of mutations in human and bacterial cells consistent with those attributed to reactive oxygen species (ROS). Studies were conducted to determine whether the oxidative stress induced by TGHQ in renal proximal tubule epithelial cells (LLC-PK1) modulates transcriptional activities widely implicated in transformation responses, namely 12-O-tetradecanoyl phorbol 13-acetate (TPA) responsive element (TRE)- and nuclear factor kappa B (NF-κB)-binding activity. TGHQ increased TRE- and NF-κB-binding activity in a concentration- and time-dependent manner. Catalase fully inhibited peak TGHQ-mediated TRE- and NF-κB-binding activity. In contrast, although deferoxamine fully inhibited TGHQ-mediated TRE-binding activity, it had only a marginal effect on NF-κB-binding activity. Collectively, these data indicate that TGHQ modulates TRE- and NF-κB-binding activity in an ROS-dependent fashion. Cycloheximide and actinomycin D fully inhibited TGHQ-mediated TRE-binding activity, but in the absence of TGHQ increased NF-κB-binding activity. Although protein kinase C (PKC) is widely implicated in stress response signaling, pretreatment of cells with PKC inhibitors (H-89, calphostin C) did not modulate TGHQ-mediated DNA-binding activities. In contrast, pretreatment of cells with (PD098059), a mitogen activated protein kinase kinase (MEK) inhibitor, markedly reduced TGHQ-mediated TRE-binding activity, but enhanced TGHQ-mediated NF-κB-binding activity. We conclude that TGHQ-mediated TRE- and NF-κB-binding activities are ROS-dependent. Although there is a common requirement for hydrogen peroxide (H2O2) in the regulation of these DNA-binding activities, there appears to be divergent regulation after H2O2 generation in renal epithelial cells.",
author = "Weber, {T. J.} and Q. Huang and Terrence Monks and Serrine Lau",
year = "2001",
doi = "10.1021/tx000190r",
language = "English (US)",
volume = "14",
pages = "814--821",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
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TY - JOUR

T1 - Differential regulation of redox responsive transcription factors by the nephrocarcinogen 2,3,5-tris(glutathion-S-yl)hydroquinone

AU - Weber, T. J.

AU - Huang, Q.

AU - Monks, Terrence

AU - Lau, Serrine

PY - 2001

Y1 - 2001

N2 - 2,3,5-Tris(glutathion-S-yl)hydroquinone [TGHQ] is a potent nephrotoxicant and nephrocarcinogen, and induces a spectrum of mutations in human and bacterial cells consistent with those attributed to reactive oxygen species (ROS). Studies were conducted to determine whether the oxidative stress induced by TGHQ in renal proximal tubule epithelial cells (LLC-PK1) modulates transcriptional activities widely implicated in transformation responses, namely 12-O-tetradecanoyl phorbol 13-acetate (TPA) responsive element (TRE)- and nuclear factor kappa B (NF-κB)-binding activity. TGHQ increased TRE- and NF-κB-binding activity in a concentration- and time-dependent manner. Catalase fully inhibited peak TGHQ-mediated TRE- and NF-κB-binding activity. In contrast, although deferoxamine fully inhibited TGHQ-mediated TRE-binding activity, it had only a marginal effect on NF-κB-binding activity. Collectively, these data indicate that TGHQ modulates TRE- and NF-κB-binding activity in an ROS-dependent fashion. Cycloheximide and actinomycin D fully inhibited TGHQ-mediated TRE-binding activity, but in the absence of TGHQ increased NF-κB-binding activity. Although protein kinase C (PKC) is widely implicated in stress response signaling, pretreatment of cells with PKC inhibitors (H-89, calphostin C) did not modulate TGHQ-mediated DNA-binding activities. In contrast, pretreatment of cells with (PD098059), a mitogen activated protein kinase kinase (MEK) inhibitor, markedly reduced TGHQ-mediated TRE-binding activity, but enhanced TGHQ-mediated NF-κB-binding activity. We conclude that TGHQ-mediated TRE- and NF-κB-binding activities are ROS-dependent. Although there is a common requirement for hydrogen peroxide (H2O2) in the regulation of these DNA-binding activities, there appears to be divergent regulation after H2O2 generation in renal epithelial cells.

AB - 2,3,5-Tris(glutathion-S-yl)hydroquinone [TGHQ] is a potent nephrotoxicant and nephrocarcinogen, and induces a spectrum of mutations in human and bacterial cells consistent with those attributed to reactive oxygen species (ROS). Studies were conducted to determine whether the oxidative stress induced by TGHQ in renal proximal tubule epithelial cells (LLC-PK1) modulates transcriptional activities widely implicated in transformation responses, namely 12-O-tetradecanoyl phorbol 13-acetate (TPA) responsive element (TRE)- and nuclear factor kappa B (NF-κB)-binding activity. TGHQ increased TRE- and NF-κB-binding activity in a concentration- and time-dependent manner. Catalase fully inhibited peak TGHQ-mediated TRE- and NF-κB-binding activity. In contrast, although deferoxamine fully inhibited TGHQ-mediated TRE-binding activity, it had only a marginal effect on NF-κB-binding activity. Collectively, these data indicate that TGHQ modulates TRE- and NF-κB-binding activity in an ROS-dependent fashion. Cycloheximide and actinomycin D fully inhibited TGHQ-mediated TRE-binding activity, but in the absence of TGHQ increased NF-κB-binding activity. Although protein kinase C (PKC) is widely implicated in stress response signaling, pretreatment of cells with PKC inhibitors (H-89, calphostin C) did not modulate TGHQ-mediated DNA-binding activities. In contrast, pretreatment of cells with (PD098059), a mitogen activated protein kinase kinase (MEK) inhibitor, markedly reduced TGHQ-mediated TRE-binding activity, but enhanced TGHQ-mediated NF-κB-binding activity. We conclude that TGHQ-mediated TRE- and NF-κB-binding activities are ROS-dependent. Although there is a common requirement for hydrogen peroxide (H2O2) in the regulation of these DNA-binding activities, there appears to be divergent regulation after H2O2 generation in renal epithelial cells.

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