Inhibitor of Nuclear Factor κB Kinase Deficiency Enhances Oxidative Stress and Prolongs c-Jun NH2-Terminal Kinase Activation Induced by Arsenic

Fei Chen, Vince Castranova, Zhiwei Li, Michael Karin, Xianglin Shi

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Stress signals activate both inhibitor of nuclear factor-κB kinase (IKKβ) and c-Jun NH2-terminal kinase (JNK). It was shown recently that IKK-dependent nuclear factor κB activation results in attenuation of tumor necrosis factor α-induced JNK activation. How that negative cross-talk between nuclear factor κB and JNK occurs is not well-understood. By using wild-type and Ikkβ gene knockout (Ikkβ -/-) mouse embryo fibroblasts, we found that IKKβ deficiency results in prolongation of arsenic-induced JNK activation, which was not due to the decreased expression of GADD45β or X-linked Inhibitor of Apoptosis (XIAP), as suggested previously for RelA-/- cells treated with tumor necrosis factor α. This enhanced JNK activation was largely associated with an oxidative stress response as indicated by elevated expression of heme oxygenase-1 and the accumulation of H2O2 in Ikkβ -/- cells. Expression profiling experiments revealed an increased expression of p450 family CYP1B1 mRNA in Ikkβ-/- cells compared with wild-type cells. Inhibition of CYP1B1 reduced both oxidative stress and arsenic-stimulated JNK activation. Thus, increased CYP1B1 expression is central to and seems to be responsible for sensitizing Ikkβ-/- cells to stress-induced JNK activation.

Original languageEnglish
Pages (from-to)7689-7693
Number of pages5
JournalCancer Research
Volume63
Issue number22
StatePublished - Nov 15 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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