Abstract
Interleukin-1 (IL-1) mediates numerous host responses through rapid activation of nuclear factor-kappaB (NF-kappaB), but signal pathways leading to the NF-kappaB activation appear to be complicated and multiplex. We propose a novel regulatory system for NF-kappaB activation by the extracellular signal-related kinase (ERK) pathway. In a human glioblastoma cell line, T98G, IL-1-induced NF-kappaB activation was significantly augmented by the pretreatment of a specific MEK inhibitor, PD98059. In contrast, ectopic expression of a constitutive activated form of Raf (v-Raf) reduced IL-1-induced NF-kappaB activation, and this inhibition was completely reversed by PD98059. Interestingly, PD98059 sustained IL-1-induced NF-kappaB DNA binding activity by an electrophoretic mobility shift assay and also IkappaBalpha degradation, presumably by augmenting and sustaining the proteasome activation. Concomitantly, two NF-kappaB dependent genes, A20 and IkappaBalpha expression were prolonged with PD98059. These data suggested that MEK-ERK pathway exerts a regulatory effect on NF-kappaB activation, providing a novel insight on the role of MEK-ERK pathway.
Copyright 2001 Academic Press.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding, Competitive / drug effects
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Cysteine Endopeptidases / metabolism
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DNA / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Dose-Response Relationship, Drug
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Enzyme Activation / drug effects
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology*
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Glioblastoma / metabolism
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Humans
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I-kappa B Kinase
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I-kappa B Proteins*
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Interleukin-1 / pharmacology*
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Intracellular Signaling Peptides and Proteins
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinases / metabolism
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Multienzyme Complexes / metabolism
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NF-KappaB Inhibitor alpha
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NF-kappa B / genetics
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NF-kappa B / metabolism*
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Nuclear Proteins
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Oncogene Proteins v-raf
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Proteasome Endopeptidase Complex
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Protein Serine-Threonine Kinases / metabolism
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Proteins / genetics
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Proteins / metabolism
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Retroviridae Proteins, Oncogenic / biosynthesis
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Retroviridae Proteins, Oncogenic / genetics
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Retroviridae Proteins, Oncogenic / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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TNF Receptor-Associated Factor 6
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Transcription Factor AP-1 / metabolism
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Transfection
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Tumor Cells, Cultured
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Tumor Necrosis Factor alpha-Induced Protein 3
Substances
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DNA-Binding Proteins
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Enzyme Inhibitors
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Flavonoids
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I-kappa B Proteins
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Interleukin-1
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Intracellular Signaling Peptides and Proteins
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Multienzyme Complexes
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NF-kappa B
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NFKBIA protein, human
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Nuclear Proteins
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Proteins
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Recombinant Fusion Proteins
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Retroviridae Proteins, Oncogenic
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TNF Receptor-Associated Factor 6
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Transcription Factor AP-1
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NF-KappaB Inhibitor alpha
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DNA
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Oncogene Proteins v-raf
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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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Mitogen-Activated Protein Kinases
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TNFAIP3 protein, human
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Tumor Necrosis Factor alpha-Induced Protein 3
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one