Inhibitor of nuclear factor kappaB kinase deficiency enhances oxidative stress and prolongs c-Jun NH2-terminal kinase activation induced by arsenic.
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.
Chen
Fei
F
Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA. lfd3@cdc.gov
Castranova
Vince
V
Li
Zhiwei
Z
Karin
Michael
M
Shi
Xianglin
X
D000818:Animals; D001151:Arsenic / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D065633:Cytochrome P-450 CYP1B1; D004622:Embryo, Mammalian; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D001189:Aryl Hydrocarbon Hydroxylases; C585498:Cyp1b1 protein, mouse; D065633:Cytochrome P-450 CYP1B1; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D001151:Arsenic