Abstract
Tumor necrosis factor receptor 1 (TNFR1) can trigger distinct signaling pathways leading to either the activation of NF-kappaB transcription factors or apoptosis. NF-kappaB activation results in the expression of antiapoptotic genes that inhibit the apoptosis pathway that is activated in parallel. However, the molecular mechanism of this inhibition remains poorly characterized. We have isolated a Jurkat T-cell mutant that exhibits enhanced sensitivity to TNF-induced apoptosis as a result of a deficiency in I-kappaB kinase gamma (IKKgamma)/NEMO, an essential component of the IKK complex and NF-kappaB pathway. We show here that the zinc finger protein A20 is an NF-kappaB-inducible gene that can protect the IKKgamma-deficient cells from TNF-induced apoptosis by disrupting the recruitment of the death domain signaling molecules TRADD and RIP to the receptor signaling complex. Our study, together with reports on the role of other antiapoptotic proteins such as c-FLIP and c-IAP, suggests that, in order to ensure an effective shutdown of the apoptotic pathway, TNF induces multiple NF-kappaB-dependent genes that inhibit successive steps in the TNFR1 death signaling pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, CD / metabolism*
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Apoptosis / drug effects*
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Caspases / physiology
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DNA-Binding Proteins
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Gene Expression Regulation, Leukemic
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Genes, Reporter
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Humans
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I-kappa B Kinase
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Intracellular Signaling Peptides and Proteins
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Jurkat Cells / drug effects
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Jurkat Cells / metabolism
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NF-kappa B / physiology
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Nuclear Proteins
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / physiology
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Protein Transport
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Proteins / metabolism*
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Proteins / physiology*
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Receptor-Interacting Protein Serine-Threonine Kinases
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor, Type I
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Signal Transduction / physiology
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T-Lymphocytes / metabolism
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TNF Receptor-Associated Factor 1
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Tetradecanoylphorbol Acetate / pharmacology
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Transcription, Genetic
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Transfection
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Tumor Necrosis Factor alpha-Induced Protein 3
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Necrosis Factor-alpha / physiology
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Zinc Fingers / physiology
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fas Receptor / physiology
Substances
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Antigens, CD
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Neoplasm Proteins
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Nuclear Proteins
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Proteins
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Receptors, Tumor Necrosis Factor
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Receptors, Tumor Necrosis Factor, Type I
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TNF Receptor-Associated Factor 1
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Tumor Necrosis Factor-alpha
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fas Receptor
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Protein Serine-Threonine Kinases
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RIPK1 protein, human
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Receptor-Interacting Protein Serine-Threonine Kinases
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CHUK protein, human
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I-kappa B Kinase
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IKBKB protein, human
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IKBKE protein, human
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3
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Caspases
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Tetradecanoylphorbol Acetate