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Protective roles of NF-kB for chromium (VI)-induced cytotoxicity is revealed by expression of IkB kinase-B mutant.

Authors
Chen-F; Bower-J; Leonard-S; Ding-M; Lu-Y; Rojanasakul-Y; Kung-H; Vallyathan-V; Castranova-V; Shi-X
Source
J Biol Chem 2002 Feb; 277(5):3342-3349
NIOSHTIC No.
20022295
Abstract
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.
Keywords
Chromium-compounds; Cytotoxicity; Carcinogenesis; Humans; Toxic-effects
Contact
PPRB of NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505
CODEN
JBCHA3
CAS No.
7440-47-3; 18540-29-9
Publication Date
20020201
Document Type
Journal Article
Email Address
xshi@cdc.gov
Funding Type
Interagency Agreement
Fiscal Year
2002
NTIS Accession No.
NTIS Price
Identifying No.
IA-98-18-00-M2
Issue of Publication
5
ISSN
0021-9258
NIOSH Division
HELD
Priority Area
Research Tools and Approaches: Cancer Research Methods
Source Name
Journal of Biological Chemistry
State
WV
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