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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis / drug effects*
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Apoptosis / genetics
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Carbazoles / pharmacology
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Caspase 8
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Caspase 9
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Caspases / metabolism
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Enzyme Activation
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Enzyme Inhibitors / pharmacology
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Fas Ligand Protein
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Gene Expression Regulation, Leukemic / physiology*
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Humans
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I-kappa B Proteins*
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Indoles / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / physiology
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Jurkat Cells / drug effects
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Jurkat Cells / metabolism
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Maleimides / pharmacology
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Membrane Glycoproteins / physiology
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NF-KappaB Inhibitor alpha
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NF-kappa B / physiology*
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Neoplasm Proteins / biosynthesis*
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Neoplasm Proteins / genetics
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / physiology
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / physiology
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Sequence Deletion
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Tetradecanoylphorbol Acetate / pharmacology*
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fas Receptor / physiology
Substances
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Carbazoles
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DNA-Binding Proteins
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Enzyme Inhibitors
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FASLG protein, human
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Fas Ligand Protein
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I-kappa B Proteins
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Indoles
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Isoenzymes
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Maleimides
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Membrane Glycoproteins
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NF-kappa B
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NFKBIA protein, human
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Neoplasm Proteins
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Recombinant Fusion Proteins
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fas Receptor
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Go 6976
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NF-KappaB Inhibitor alpha
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Protein Kinase C
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CASP8 protein, human
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CASP9 protein, human
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Caspase 8
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Caspase 9
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Caspases
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bisindolylmaleimide I
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Tetradecanoylphorbol Acetate