Abstract
RKIP was first identified as an inhibitor of the Raf-MEK-ERK signaling pathway. RKIP was also found to play an important role in the NF-kappaB pathway. Genetic and biochemical studies demonstrated that RKIP functioned as a scaffold protein facilitating the phosphorylation of IkappaB by upstream kinases. However, contrary to what one would expect of a scaffold protein, our results show that RKIP has an overall inhibitory effect on the NF-kappaB transcriptional activities. Since NF-kappaB target gene expression is subject to negative regulation involving the optimal induction of negative regulators, our data support a hypothesis that RKIP inhibits NF-kappaB activity via the auto-regulatory feedback loop by rapidly inducing the expression and synthesis of inhibitors of NF-kappaB activation.
Copyright 2009 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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COS Cells
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Cell Line
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Cell Line, Tumor
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Chlorocebus aethiops
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Gene Expression / drug effects
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Humans
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I-kappa B Kinase / metabolism*
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I-kappa B Proteins / metabolism
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Immunoblotting
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Immunoprecipitation
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Interleukin-1 Receptor-Associated Kinases / metabolism
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Interleukin-1beta / pharmacology
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MAP Kinase Kinase Kinases / metabolism
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NF-KappaB Inhibitor alpha
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NF-kappa B / metabolism*
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Neoplasms / genetics
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Neoplasms / metabolism
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Neoplasms / pathology
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Phosphatidylethanolamine Binding Protein / genetics
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Phosphatidylethanolamine Binding Protein / metabolism*
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Phosphorylation / drug effects
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Protein Binding
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction*
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TNF Receptor-Associated Factor 6 / metabolism
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Ubiquitination / drug effects
Substances
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I-kappa B Proteins
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Interleukin-1beta
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NF-kappa B
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NFKBIA protein, human
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PEBP1 protein, human
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Phosphatidylethanolamine Binding Protein
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TNF Receptor-Associated Factor 6
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NF-KappaB Inhibitor alpha
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Interleukin-1 Receptor-Associated Kinases
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I-kappa B Kinase
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MAP Kinase Kinase Kinases
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MAP kinase kinase kinase 7