ToxSci Advance Access originally published online on September 16, 2004
Toxicological Sciences 2004 82(2):638-646; doi:10.1093/toxsci/kfh278
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Toxicological Sciences vol. 82 no. 2 © Society of Toxicology 2004; all rights reserved.
The Role of Hypoxia Inducible Factor 1
in Cobalt Chloride Induced Cell Death in Mouse Embryonic Fibroblasts
,
,1
* Department of Biochemistry and Molecular Biology, Graduate Program in Genetics, National Food Safety and Toxicology Center, and Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan 48824-1319
Received May 25, 2004; accepted September 3, 2004
Cobalt has been widely used in the treatment of anemia and as a hypoxia mimic in cell culture and it is known to activate hypoxic signaling by stabilizing the hypoxia inducible transcription factor 1
(HIF1). However, cobalt exposure can lead to tissue and cellular toxicity. These studies were conducted to determine the role of HIF1 in mediating cobalt-induced toxicity. Mouse embryonic fibroblasts (MEFs) that were null for the HIF1 protein were used to show that HIF1 protein plays a major role in mediating cobalt-induced cytotoxicity. Previous work from our lab and others has shown that two BH3 domain containing cell death genes, BNip3 and NIX, are targets of hypoxia signaling. These experiments document that BNip3 and NIX expression is HIF1-dependent, and cobalt induces their expression in a time and dose dependent manner. In addition, their expression is correlated with an increase in BNIP3 and NIX protein. Characteristically, the elevated level of BNIP3 was correlated with an increased presence of chromatin condensation, one marker for cell injury. Interestingly, this increased chromosomal condensation was not coupled to caspase-3 activation as usually seen in a typical apoptotic response. These results show that HIF1 is playing a major role in mediating cobalt-induced toxicity in mouse embryonic fibroblasts and may offer a possible mechanism for the underlying pathology of injuries seen in workers exposed to environmental contaminants that can influence the hypoxia signaling system, such as cobalt.
Key Words: cobalt; hypoxia; toxicity; BNIP3; metal.
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