title: Blocking NF-kappaB activation in Jurkat leukemic T cells converts the survival agent and tumor promoter PMA into an apoptotic effector.
abstract: The transcription factor NF-kappaB promotes cell survival. Using a variant of Jurkat leukemic T cells expressing IkappaB-alphaDeltaN, a super-repressor of NF-kappaB activation we first show that the tumor promoter PMA could prevent Fas-induced apoptosis via activation of NF-kappaB. Moreover, we demonstrate that in the absence of NF-kappaB activation, PMA became a strong inducer of apoptosis through stimulation of the upstream caspases 8 and 9 as well as of the effector caspase 3. A RNase-protection analysis showed that PMA stimulated the expression of several known anti-apoptotic genes (TRAF1, TRAF4, c-IAP-1, c-IAP-2, Bfl-1, Bcl-xl). In the absence of NF-kappaB activation, these survival influences were strongly lowered revealing the apoptotic effect of PMA. These results suggest that NF-kappaB activation could be an important step in the tumor promoting effect of PMA.
authors.affiliation: INSERM U526, Activation des Cellules Hématopoïétiques, Physiologie de la Survie et de la Mort Cellulaires et Infections Virales, IFR 50 Génétique et Signalisation Moléculaires, Faculté de Médicine Pasteur, 06107 Nice cedex 02, France.
authors.forename: Valère
authors.initials: V
authors.lastname: Busuttil
authors.forename: Virginie
authors.initials: V
authors.lastname: Bottero
authors.forename: Catherine
authors.initials: C
authors.lastname: Frelin
authors.forename: Véronique
authors.initials: V
authors.lastname: Imbert
authors.forename: Jean-Erhland
authors.initials: JE
authors.lastname: Ricci
authors.forename: Patrick
authors.initials: P
authors.lastname: Auberger
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Peyron
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002227:Carbazoles / Q000494:pharmacology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053222:Fas Ligand Protein; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins; D007211:Indoles / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D008301:Maleimides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000502:physiology*; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D017384:Sequence Deletion; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology
chemical_list: D002227:Carbazoles; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D020672:I-kappa B Proteins; D007211:Indoles; D007527:Isoenzymes; D008301:Maleimides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; C081021:Go 6976; D000072000:NF-KappaB Inhibitor alpha; D011493:Protein Kinase C; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate