A MEK inhibitor, PD98059 enhances IL-1-induced NF-kappaB activation by the enhanced and sustained degradation of IkappaBalpha.
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.
Funakoshi
M
M
Department of Biochemistry and Immunology, Kyoritsu College of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo, 105-8512, Japan.
Tago
K
K
Sonoda
Y
Y
Tominaga
S
S
Kasahara
T
T
D001667:Binding, Competitive / Q000187:drug effects; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D027384:Oncogene Proteins v-raf; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D020672:I-kappa B Proteins; D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D009687:Nuclear Proteins; D011506:Proteins; D011993:Recombinant Fusion Proteins; D015682:Retroviridae Proteins, Oncogenic; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D027384:Oncogene Proteins v-raf; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D020928:Mitogen-Activated Protein Kinases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one