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A MEK Inhibitor, PD98059 Enhances IL-1-Induced NF-κB Activation by the Enhanced and Sustained Degradation of IκBα

https://doi.org/10.1006/bbrc.2001.4759Get rights and content

Abstract

Interleukin-1 (IL-1) mediates numerous host responses through rapid activation of nuclear factor-κB (NF-κB), but signal pathways leading to the NF-κB activation appear to be complicated and multiplex. We propose a novel regulatory system for NF-κB activation by the extracellular signal-related kinase (ERK) pathway. In a human glioblastoma cell line, T98G, IL-1-induced NF-κB 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-κB activation, and this inhibition was completely reversed by PD98059. Interestingly, PD98059 sustained IL-1-induced NF-κB DNA binding activity by an eletrophoretic mobility shift assay and also IκBα degradation, presumably by augmenting and sustaining the proteasome activation. Concomitantly, two NF-κB dependent genes, A20 and IκBα expression were prolonged with PD98059. These data suggested that MEK-ERK pathway exerts a regulatory effect on NF-κB activation, providing a novel insight on the role of MEK-ERK pathway.

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    BRAFV600E mutation also activates IκBα and causes activation of NF-κB [20]. The MAPK pathway plays a regulatory role in NF-κB activation, and the MEK inhibitor (PD98059) has been reported to induce NF-κB activation by augmenting IκB degradation [32] or increasing IκB phosphorylation [33]. Prior studies showed that the combination of MEK inhibitor (PD0325901) and NF-κB pathway inhibitor (PS1145) was associated with a synergistic inhibition in TC cells [34], although these inhibitors are not currently applicable in the clinical setting.

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