title: The mutant plasmacytoma cell line S107 allows the identification of distinct pathways leading to NF-kappaB activation.
abstract: Studies on the mechanisms of inducible and constitutive activity of NF-kappaB transcription factors have been hampered by the lack of appropriate mutant cell lines. We have analyzed the defect in the murine S107 plasmacytoma cell line, which was previously found to lack both constitutive and inducible NF-kappaB activity. Our analysis shows that these cells bear a specific defect that interferes with NF-kappaB induction by many diverse stimuli, such as lipopolysaccharide, phorbol 12-myristate 13-acetate, UV light, x-rays, and H2O2. This does not however represent a general signal transduction defect, because AP-1 transcription factors are readily induced by the same stimuli. Phosphatase inhibitors such as okadaic acid as well as calyculin A can efficiently induce NF-kappaB in S107 cells via a pathway apparently insensitive to the radical scavenger pyrrolidine dithiocarbamate. Furthermore, MEKK1 a protein kinase supposedly induced by some of the above stimuli, is also capable of activating NF-kappaB. Interestingly, both the potent physiological inducer of NF-kappaB TNFalpha as well as endoplasmic reticulum overload can induce NF-kappaB via a PDTC sensitive pathway. In all cases, DNA-binding NF-kappaB complexes are comprised predominantly of p50-RelA heterodimers, and NF-kappaB activation results in the induction of transiently transfected or resident reporter genes. In summary, these results suggest that the pathways for many NF-kappaB-inducing stimuli converge at a specific junction, and this pivotal step is mutated in the S107 cell line. Yet there are alternative routes bypassing this critical step that also lead to NF-kappaB induction. These routes utilized by tumor necrosis factor alpha and endoplasmic reticulum overload are still intact in this cell line.
authors.affiliation: Institut für Medizinische Strahlenkunde und Zellforschung, Universität Würzburg, Versbacher Strasse 5, 97078 Würzburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Baumann
authors.forename: B
authors.initials: B
authors.lastname: Kistler
authors.forename: A
authors.initials: A
authors.lastname: Kirillov
authors.forename: Y
authors.initials: Y
authors.lastname: Bergman
authors.forename: T
authors.initials: T
authors.lastname: Wirth
mesh_terms: D000818:Animals; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D020672:I-kappa B Proteins; D048728:MAP Kinase Kinase Kinase 1; D008387:Marine Toxins; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D010954:Plasmacytoma / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D011759:Pyrrolidines / Q000494:pharmacology; D015398:Signal Transduction; D013859:Thiocarbamates / Q000494:pharmacology; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D020672:I-kappa B Proteins; D008387:Marine Toxins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; D010080:Oxazoles; D011518:Proto-Oncogene Proteins; D011759:Pyrrolidines; C497594:Relb protein, mouse; D013859:Thiocarbamates; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D051841:Transcription Factor RelB; D019319:Okadaic Acid; C020972:pyrrolidine dithiocarbamic acid; C059041:calyculin A; D004247:DNA; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D010749:Phosphoprotein Phosphatases