Suboptimal Action of NF-κB in Fanconi Anemia Cells Results from Low Levels of Thioredoxin
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M. Kontou
Abstract
Electrophoretic mobility shift assays (EMSA) revealed that under standard cell culture conditions NF-κB was induced in Fanconi anemia fibroblasts in contrast to control cells. Dithiothreitol, a potent synthetic redox potential-delivering compound, when added to growing cells, prevented this induction of NF-κB and, simultaneously, chromosomal instability was reduced. Fanconi anemia cells possess low endogenous levels of the naturally occurring antioxidant thioredoxin. Transfection of Fanconi anemia cells with thioredoxin cDNA containing a nuclear localization signal prevented both spontaneous as well as mitomycin Cinduced chromosomal instability. A promotor construct with two NF-κB binding sites in front of the CAT gene induced little CAT expression in cells with low thioredoxin content in spite of induced NF-κB. In cells with higher thioredoxin content CAT expression was increased. Cotransfection of the NF-κB-dependent CAT plasmid with the Trx/nuc-plasmid into FA fibroblasts increased the CAT expression to almost that of control cells, indicating that in this model system with diminished thioredoxin content NF-κB requires thioredoxin for binding to its specific promotor. Since Fanconi anemia cells have low thioredoxin contents, NF-κB-dependent genes are expressed insufficiently. This explains part of the pathophysiological processes observed in Fanconi anemia.
Copyright © 2003 by Walter de Gruyter GmbH & Co. KG
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- Ribosomal Tolerance and Peptide Bond Formation
- Transcription of Cathepsin B in Glioma Cells: Regulation by an E-Box Adjacent to the Transcription Initiation Site
- The Catalytically Active Domain in the A Subunit of Calcineurin
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