To delineate the molecular mechanisms of NF-B-mediated regulation of chromium(VI)-induced cell death, the signaling pathway leading to the activation of NF-B was interrupted by stable transfection of a kinase-mutated form of IB kinase (IKK-KM). Here we demonstrate a novel role for the NF-B transcription factor in inhibiting chromium(VI)-induced cell death. Inhibition of NF-B by IKK-KM or IKK gene deficiency resulted in a spontaneous cleavage of Bcl-xl antiapoptotic protein due to the elevated caspase-3 activity. DNA microarray assay suggested a decreased expression of genes encoding antiapoptotic proteins, cIAP1 and cIAP2, in the cells overexpressing IKK-KM. Chromium(VI) treatment of these NF-B-inhibited cells induced necrotic-like cell death. Such chromium(VI)-induced cell killing could be partially inhibited by expression of exogenous cIAP1, an inhibitor of caspases, indicating that caspases along with others may be involved in chromium(VI)-induced cell death. These results suggest that NF-B is essential for inhibiting toxic metal-induced cytotoxicity. Such inhibition may involve up-regulation of the expression of anti-death proteins including cIAP1 that prevents spontaneous caspase activation and subsequent cleavage of Bcl-xl protein.
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