TY - JOUR
T1 - A MEK inhibitor, PD98059 enhances IL-1-induced NF-κB activation by the enhanced and sustained degradation of IκBα
AU - Funakoshi, Megumi
AU - Tago, Kenji
AU - Sonoda, Yoshiko
AU - Tominaga, Shin ichi
AU - Kasahara, Tadashi
PY - 2001/1/1
Y1 - 2001/1/1
N2 - 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.
AB - 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.
KW - ERK
KW - Interleukin-1
KW - IκBα
KW - MEK
KW - NF-κB
KW - PD98059
KW - Proteasome
UR - http://www.scopus.com/inward/record.url?scp=0034789898&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034789898&partnerID=8YFLogxK
U2 - 10.1006/bbrc.2001.4759
DO - 10.1006/bbrc.2001.4759
M3 - Article
C2 - 11322796
AN - SCOPUS:0034789898
VL - 283
SP - 248
EP - 254
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -