Protective roles of NF-κB for chromium (VI)-induced cytotoxicity is revealed by expression of IκB kinase-β mutant

被引:30
作者
Chen, F
Bower, J
Leonard, SS
Ding, M
Lu, YJ
Rojanasakul, Y
Kung, HF
Vallyathan, V
Castranova, V
Shi, XL
机构
[1] NIOSH, PPRB, Hlth Effects Lab Div, Morgantown, WV 26505 USA
[2] W Virginia Univ, Dept Basic Pharmaceut Sci, Morgantown, WV 26506 USA
[3] Univ Hong Kong, Inst Mol Biol, Hong Kong, Hong Kong, Peoples R China
关键词
D O I
10.1074/jbc.M101089200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
To delineate the molecular mechanisms of NF-KE-mediated regulation of chromium (VI)-induced cell death, the signaling pathway leading to the activation of NF-KB was interrupted by stable transfection of a kinase-mutated form of IKB kinase beta (IKKbeta-KM). Here we demonstrate a novel role for the NF-KB transcription factor in inhibiting chromium (VI) -induced cell death. Inhibition of NF-KB by IKKbeta-KM or IKKbeta gene deficiency resulted in a spontaneous cleavage of Bel-xl antiapoptotic protein due to the elevated caspase-3 activity. DNA microarray assay suggested a decreased expression of genes encoding antiapoptotic proteins, cLAP1 and cLAP2, in the cells overexpressing IKKbeta-KM. Chromium(VI) treatment of these NF-KB-inhibited cells induced necrotic-like cell death. Such chromium(VI) -induced cell killing could be partially inhibited by expression of exogenous cLAP1, an inhibitor of caspases, indicating that caspases along with others may be involved in chromium(VI)induced cell death. These results suggest that NF-KB is essential for inhibiting toxic metal-induced cytotoxicity. Such inhibition may involve up-regulation of the expression of anti-death proteins including cLAP1 that prevents spontaneous caspase activation and subsequent cleavage of Bel-xl protein.
引用
收藏
页码:3342 / 3349
页数:8
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