MEK kinase is involved in tumor necrosis factor α-induced NF-kB activation and degradation of IκB-α

Abstract

Signal-dependent activation of the transcription factor NF-κB is dominantly regulated by degradation of IκB-α 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 NTH3T3 fibroblasts activates κB-CAT reporter expression in a synergistic manner with TNFα stimulation. In contrast, overexpression of kinase-negative MEK kinase suppresses TNFa-induced reporter expression. The overexpression of MEK kinase suppresses the inhibitory activity of co-transfected IκB-α on the κB-CAT or human immunodeficiency virus-long terminal repeat-luciferase reporter expression and causes the simultaneous disappearance of the overexpressed IκB-α. The disappearance of exogenous IκB-α by the overexpression of MEK kinase is prevented by calpain inhibitor-I, an inhibitor of IκB-α degradation. These results suggest that MEK kinase is a signal mediator involved in TNFα-induced NF-κB activation and that the activation of NF-κB by MEK kinase is regulated through the degradation of IκB-α.