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Suboptimal action of NF-kappa B in Fanconi anemia cells results from low levels of thioredoxin

MPG-Autoren
http://pubman.mpdl.mpg.de/cone/persons/resource/persons50053

Adelfalk,  Caroline
Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Zitation

Kontou, M., Adelfalk, C., Hirsch-Kauffmann, M., & Schweiger, M. (2003). Suboptimal action of NF-kappa B in Fanconi anemia cells results from low levels of thioredoxin. Biological Chemistry, 384(10-11), 1501-1507.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-0010-89A2-A
Zusammenfassung
Electrophoretic mobility shift assays (EMSA) revealed that under standard cell culture conditions NF- B 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- B 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 C-induced chromosomal instability. A promotor construct with two NF- B binding sites in front of the CAT gene induced little CAT expression in cells with low thioredoxin content in spite of induced NF-[kappa]B. In cells with higher thioredoxin content CAT expression was increased. Cotransfection of the NF-[kappa]B-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-[kappa]B requires thioredoxin for binding to its specific promotor. Since Fanconi anemia cells have low thioredoxin contents, NF-[kappa]B-dependent genes are expressed insufficiently. This explains part of the pathophysiological processes observed in Fanconi anemia.