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

¹ Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia,
² Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California

Stress signals activate both inhibitor of nuclear factor-B kinase (IKKß) and c-Jun NH₂-terminal kinase (JNK). It was shown recently that IKK-dependent nuclear factor B activation results in attenuation of tumor necrosis factor -induced JNK activation. How that negative cross-talk between nuclear factor B and JNK occurs is not well-understood. By using wild-type and Ikkß gene knockout (Ikkß^-/-) mouse embryo fibroblasts, we found that IKKß deficiency results in prolongation of arsenic-induced JNK activation, which was not due to the decreased expression of GADD45ß or X-linked Inhibitor of Apoptosis (XIAP), as suggested previously for RelA^-/- cells treated with tumor necrosis factor . 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 Ikkß^-/- cells. Expression profiling experiments revealed an increased expression of p450 family CYP1B1 mRNA in Ikkß^-/- 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 Ikkß^-/- cells to stress-induced JNK activation.

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