Abstract
A myriad of stimuli including proinflammatory cytokines, viruses, and chemical and mechanical insults activate a kinase complex composed of IkappaB kinase beta (IKK-beta), IKK-alpha, and IKK-gamma/N, leading to changes in NF-kappaB-dependent gene expression. However, it is not clear how the NF-kappaB response is tailored to specific cellular insults. Signaling molecule that interacts with mouse pelle-like kinase (SIMPL) is a signaling component required for tumor necrosis factor alpha (TNF-alpha)-dependent but not interleukin-1-dependent NF-kappaB activation. Herein we demonstrate that nuclear localization of SIMPL is required for type I TNF receptor-induced NF-kappaB activity. SIMPL interacts with nuclear p65 in a TNF-alpha-dependent manner to promote endogenous NF-kappaB-dependent gene expression. The interaction between SIMPL and p65 enhances p65 transactivation activity. These data support a model in which TNF-alpha activation of NF-kappaB dependent-gene expression requires nuclear relocalization of p65 as well as nuclear relocalization of SIMPL, generating a TNF-alpha-specific induction of gene expression.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / metabolism
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Carrier Proteins / chemistry
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Cell Line
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Cell Nucleus / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins
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Mice
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Molecular Sequence Data
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Multiprotein Complexes
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NF-kappa B / agonists
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NF-kappa B / chemistry
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NF-kappa B / metabolism*
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Nuclear Localization Signals / chemistry
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Protein Structure, Tertiary
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Protein Transport
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Proto-Oncogene Proteins c-jun / genetics
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Proto-Oncogene Proteins c-jun / metabolism
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Receptors, Tumor Necrosis Factor, Type I / metabolism
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Transcription Factor RelA
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Transcriptional Activation
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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CCAAT-Enhancer-Binding Proteins
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Carrier Proteins
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Intracellular Signaling Peptides and Proteins
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Multiprotein Complexes
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NF-kappa B
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Nuclear Localization Signals
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Proto-Oncogene Proteins c-jun
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Receptors, Tumor Necrosis Factor, Type I
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SIMPL protein, mouse
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Transcription Factor RelA
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Tumor Necrosis Factor-alpha