A critical role for IkappaB kinase beta in metallothionein-1 expression and protection against arsenic toxicity.
Arsenic is a widespread environmental toxic agent that has been shown to cause diverse tissue and cell damage and at the same time to be an effective anti-cancer therapeutic agent. The objective of this study is to explore the signaling mechanisms involved in arsenic toxicity. We show that the IkappaB kinase beta (IKKbeta) plays a crucial role in protecting cells from arsenic toxicity. Ikkbeta(-)(/)(-) mouse 3T3 fibroblasts have decreased expression of antioxidant genes, such as metallothionein 1 (Mt1). In contrast to wild type and IKKbeta-reconstituted Ikkbeta(-)(/)(-) cells, IKKbeta-null cells display a marked increase in arsenic-induced reactive oxygen species (ROS) accumulation, which leads to activation of the MKK4-c-Jun NH(2)-terminal kinase (JNK) pathway, c-Jun phosphorylation, and apoptosis. Pretreatment with the antioxidant N-acetylcysteine (NAC) and expression of MT1 in the Ikkbeta(-)(/)(-) cells prevented JNK activation; moreover, NAC pretreatment, MT1 expression, MKK4 ablation, and JNK inhibition all protected cells from death induced by arsenic. Our data show that two signaling pathways appear to be important for modulating arsenic toxicity. First, the IKK-NF-kappaB pathway is crucial for maintaining cellular metallothionein-1 levels to counteract ROS accumulation, and second, when this pathway fails, excessive ROS leads to activation of the MKK4-JNK pathway, resulting in apoptosis.
Peng
Zhimin
Z
Department of Environmental Health, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, USA.
Peng
Li
L
Fan
Yunxia
Y
Zandi
Ebrahim
E
Shertzer
Howard G
HG
Xia
Ying
Y
D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D001151:Arsenic / Q000494:pharmacology* / Q000633:toxicity; D018053:Arsenites / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D051550:I-kappa B Kinase / Q000378:metabolism / Q000502:physiology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008668:Metallothionein / Q000737:chemistry*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D000970:Antineoplastic Agents; D018053:Arsenites; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D008668:Metallothionein; D051550:I-kappa B Kinase; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; C015001:arsenite; D001151:Arsenic