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Inhibitor of nuclear factor kB kinase deficiency enhances oxidative stress and prolongs c-Jun NH2-terminal kinase activation induced by arsenic.

Authors
Chen-F; Castranova-V; Li-Z; Karin-M; Shi-X
Source
Cancer Res 2003 Nov; 63(22):7689-7693
NIOSHTIC No.
20023885
Abstract
Stress signals activate both inhibitor of nuclear factor-kappaB kinase (IKKbeta) and c-Jun NH(2)-terminal kinase (JNK). It was shown recently that IKK-dependent nuclear factor kappaB activation results in attenuation of tumor necrosis factor alpha-induced JNK activation. How that negative cross-talk between nuclear factor kappaB and JNK occurs is not well-understood. By using wild-type and Ikkbeta gene knockout (Ikkbeta(-/-)) mouse embryo fibroblasts, we found that IKKbeta deficiency results in prolongation of arsenic-induced JNK activation, which was not due to the decreased expression of GADD45beta or X-linked Inhibitor of Apoptosis (XIAP), as suggested previously for RelA(-/-) cells treated with tumor necrosis factor alpha. 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 H(2)O(2) in Ikkbeta(-/-) cells. Expression profiling experiments revealed an increased expression of p450 family CYP1B1 mRNA in Ikkbeta(-/-) 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 Ikkbeta(-/-) cells to stress-induced JNK activation.
Keywords
Oxidative-processes; Stress; Arsenic-compounds; Sensitization; Laboratory-animals; Animal-studies; Animals; Hydrocarbons
Contact
Fei Chen, Health Effects Laboratory Division, NIOSH, PPRB, 1095 Willowdale Road, Morgantown, WV 26505
CODEN
CNREA8
CAS No.
7440-38-2
Publication Date
20031115
Document Type
Journal Article
Fiscal Year
2004
NTIS Accession No.
NTIS Price
Issue of Publication
22
ISSN
0008-5472
NIOSH Division
HELD
Source Name
Cancer Research
State
WV; CA
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