Abstract
Tumor necrosis factor-alpha (TNF-alpha) and lymphotoxin-beta receptor (LTbetaR) signaling both play important roles in inflammatory and immune responses through activation of NF-kappaB. Using various deficient mouse embryonic fibroblast cells, we have compared the signaling pathways leading to NF-kappaB induction in response to TNF-alpha and LTbetaR activation. We demonstrate that LTbetaR ligation induces not only RelA/p50 dimers but also RelB/p50 dimers, whereas TNF-alpha induces only RelA/p50 dimers. LTbetaR-induced binding of RelB/p50 requires processing of p100 that is mediated by IKKalpha but is independent of IKKbeta, NEMO/IKKgamma, and RelA. Moreover, we show that RelB, p50, and p100 can associate in the same complex and that TNF-alpha but not LTbeta signaling increases the association of p100 with RelB/p50 dimers in the nucleus, leading to the specific inhibition of RelB DNA binding. These results suggest that the alternative NF-kappaB pathway based on p100 processing may account not only for the activation of RelB/p52 dimers but also for that of RelB/p50 dimers and that p100 regulates the binding activity of RelB/p50 dimers via at least two distinct mechanisms depending on the signaling pathway involved.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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DNA / metabolism
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Dimerization
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Endonucleases
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Fibroblasts / metabolism
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Gene Expression Regulation
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I-kappa B Kinase
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I-kappa B Proteins / metabolism
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Lymphotoxin beta Receptor
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Mice
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NF-kappa B / metabolism*
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NF-kappa B p50 Subunit
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Nuclear Proteins / metabolism
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Nuclear Proteins / physiology*
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism*
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Receptors, Tumor Necrosis Factor / metabolism*
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Receptors, Tumor Necrosis Factor / physiology
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Transcription Factor RelB
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism*
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Tumor Necrosis Factor-alpha / physiology*
Substances
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I-kappa B Proteins
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Ltbr protein, mouse
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Lymphotoxin beta Receptor
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NF-kappa B
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NF-kappa B p50 Subunit
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Nuclear Proteins
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Proto-Oncogene Proteins
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Receptors, Tumor Necrosis Factor
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Relb protein, mouse
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Transcription Factor RelB
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DNA
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Protein Serine-Threonine Kinases
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Chuk protein, mouse
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I-kappa B Kinase
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Ikbkb protein, mouse
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Ikbke protein, mouse
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Endonucleases
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Snd1 protein, mouse