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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
7
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pubmed:dateCreated |
2002-3-22
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pubmed:abstractText |
Exposure of HepG2 cells to nonsteroidal anti-inflammatory drugs (i.e., indomethacin and ibuprofen; NSAIDs) as well as resveratrol, caused increased expression of the mRNAs coding for the catalytic (Gclc) and modifier (Gclm) subunits of the glutathione synthetic enzyme, gamma-glutamylcysteine synthetase. In addition, indomethacin exposure increased intracellular glutathione content as well as inhibited glutathione depletion and cytotoxicity caused by diethyl maleate. Indomethacin-induced increases in the expression of gamma-glutamylcysteine synthetase mRNA were preceded by increases in steady state levels of intracellular pro-oxidants and glutathione disulfide accumulation. Simultaneous incubation with the thiol antioxidant N-acetylcysteine (NAC) inhibited indomethacin-mediated increases in GCLC mRNA, suggesting that increases in GCLC message were triggered by changes in intracellular oxidation/reduction (redox) reactions. Indirect immunofluorescence using intact cells demonstrated that indomethacin induced the nuclear translocation of Nrf2, a transcription factor believed to regulate GCLC expression. Immunoprecipitation studies showed that indomethacin treatment also inhibited Nrf2 tethering to KIAA0132 (the human homolog of Keap1 accession #D50922), which is believed to be a negative regulator of Nrf2. Consistent with this idea, over-expression of Nrf2 increased GCLC reporter gene expression and over-expression of KIAA0132 inhibited GCLC reporter gene activity as well as inhibited indomethacin-induced increases in the expression of GCLC. Finally, simultaneous treatment with NAC inhibited both indomethacin-induced release of Nrf2 from KIAA0132 and indomethacin-induced nuclear translocation of Nrf2. These results demonstrate that NSAIDs and resveratrol cause increases in the expression of gamma-glutamylcysteine synthetase mRNA and identify these agents as being capable of stimulating glutathione metabolism. These results also support the hypothesis that indomethacin-induced transcriptional activation of GCLC involves the redox-dependent release of KIAA0132 from Nrf2 followed by the nuclear translocation of Nrf2.
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pubmed:grant |
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pubmed:commentsCorrections |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Inflammatory Agents...,
http://linkedlifedata.com/resource/pubmed/chemical/Carrier Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Chloramphenicol O-Acetyltransferase,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Glutamate-Cysteine Ligase,
http://linkedlifedata.com/resource/pubmed/chemical/Glutathione,
http://linkedlifedata.com/resource/pubmed/chemical/Ibuprofen,
http://linkedlifedata.com/resource/pubmed/chemical/Indomethacin,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/MAP2K1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Map2k1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/NF-E2-Related Factor 2,
http://linkedlifedata.com/resource/pubmed/chemical/NFE2L2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Trans-Activators
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0891-5849
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pubmed:author |
pubmed-author:FreemanMichael LML,
pubmed-author:GiusDavidD,
pubmed-author:GuisDavidD,
pubmed-author:HarrisStephanieS,
pubmed-author:HoltJeffrey TJT,
pubmed-author:MarnettLawrence JLJ,
pubmed-author:MeredithMichael JMJ,
pubmed-author:NguyenTrung TTT,
pubmed-author:SekharKonjeti RKR,
pubmed-author:SpitzDouglas RDR,
pubmed-author:SummarMarshall LML
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
32
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
650-62
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:11909699-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:11909699-Blotting, Northern,
pubmed-meshheading:11909699-Carcinoma, Hepatocellular,
pubmed-meshheading:11909699-Carrier Proteins,
pubmed-meshheading:11909699-Chloramphenicol O-Acetyltransferase,
pubmed-meshheading:11909699-DNA-Binding Proteins,
pubmed-meshheading:11909699-Fluorescent Antibody Technique, Indirect,
pubmed-meshheading:11909699-Glutamate-Cysteine Ligase,
pubmed-meshheading:11909699-Glutathione,
pubmed-meshheading:11909699-Humans,
pubmed-meshheading:11909699-Ibuprofen,
pubmed-meshheading:11909699-Indomethacin,
pubmed-meshheading:11909699-Leucine Zippers,
pubmed-meshheading:11909699-Liver Neoplasms,
pubmed-meshheading:11909699-MAP Kinase Kinase 1,
pubmed-meshheading:11909699-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:11909699-NF-E2-Related Factor 2,
pubmed-meshheading:11909699-Oxidation-Reduction,
pubmed-meshheading:11909699-Promoter Regions, Genetic,
pubmed-meshheading:11909699-Protein-Serine-Threonine Kinases,
pubmed-meshheading:11909699-RNA, Messenger,
pubmed-meshheading:11909699-Trans-Activators,
pubmed-meshheading:11909699-Transfection,
pubmed-meshheading:11909699-Tumor Cells, Cultured
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pubmed:year |
2002
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pubmed:articleTitle |
Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase.
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pubmed:affiliation |
Dept of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.
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