MEK kinase is involved in tumor necrosis factor alpha-induced NF-kappaB activation and degradation of IkappaB-alpha.
Signal-dependent activation of the transcription factor NF-kappaB is dominantly regulated by degradation of IkappaB-alpha protein. However, the signaling pathways that lead to the degradation are not clear. Here we report that mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) kinase, an activator of stress-activated protein kinases/jun kinase-1 (SAPKs/JNK1), is involved in such signaling pathways. The transient overexpression of MEK kinase in NIH3T3 fibroblasts activates kappaB-CAT reporter expression in a synergistic manner with TNFalpha stimulation. In contrast, overexpression of kinase-negative MEK kinase suppresses TNFalpha-induced reporter expression. The overexpression of MEK kinase suppresses the inhibitory activity of co-transfected IkappaB-alpha on the kappaB-CAT or human immunodeficiency virus-long terminal repeat-luciferase reporter expression and causes the simultaneous disappearance of the overexpressed IkappaB-alpha. The disappearance of exogenous IkappaB-alpha by the overexpression of MEK kinase is prevented by calpain inhibitor-I, an inhibitor of IkappaB-alpha degradation. These results suggest that MEK kinase is a signal mediator involved in TNFalpha-induced NF-kappaB activation and that the activation of NF-kappaB by MEK kinase is regulated through the degradation of IkappaB-alpha.
Hirano
M
M
Department of Molecular Biology, Yokohama City University School of Medicine, 3-9 Fuku-ura, Kanazawa-ku, Yokohama 236, Japan.
Osada
S
S
Aoki
T
T
Hirai
S
S
Hosaka
M
M
Inoue
J
J
Ohno
S
S
D016475:3T3 Cells; D000818:Animals; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D020672:I-kappa B Proteins; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014466:Ultraviolet Rays
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D017346:Protein Serine-Threonine Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse