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Eukaryotic translation initiation factor 4E is a cellular target for toxicity and death due to exposure to cadmium chloride.
Othumpangat-S; Kashon-M; Joseph-P
J Biol Chem 2005 Jul; 280(26):25162-25169
Whether translation initiation factor 4E (eIF4E), the mRNA cap binding and rate-limiting factor required for translation, is a target for cytotoxicity and cell death induced by cadmium, a human carcinogen, was investigated. Exposure of human cell lines, HCT15, PLC/PR/5, HeLa, and Chang, to cadmium chloride resulted in cytotoxicity and cell death, and this was associated with a significant decrease in eIF4E protein levels. Similarly, specific silencing of the expression of the eIF4E gene, caused by a small interfering RNA, resulted in significant cytotoxicity and cell death. On the other hand, overexpression of the eIF4E gene was protective against the cadmium-induced cytotoxicity and cell death. Further studies revealed the absence of alterations in the eIF4E mRNA level in the cadmium-treated cells despite their decreased eIF4E protein level. In addition, exposure of cells to cadmium resulted in enhanced ubiquitination of eIF4E protein while inhibitors of proteasome activity reversed the cadmium-induced decrease of eIF4E protein. Exposure of cells to cadmium, as well as the specific silencing of eIF4E gene, also resulted in decreased cellular levels of cyclin D1, a critical cell cycle and growth regulating gene, suggesting that the observed inhibition of cyclin D1 gene expression in the cadmium-treated cells is most likely due to decreased cellular level of eIF4E. Taken together, our results demonstrate that the exposure of cells to cadmium chloride resulted in cytotoxicity and cell death due to enhanced ubiquitination and consequent proteolysis of eIF4E protein, which in turn diminished cellular levels of critical genes such as cyclin D1.
Cadmium-compounds; Mortality-data; Mortality-rates; Exposure-levels; Cytotoxicity; Cytotoxic-effects; Cell-damage; Carcinogens; Carcinogenicity; Carcinogenesis; Genes
MS 3014, Molecular Carcinogenesis Laboratory, Toxicology and Molecular Biology Branch, CDC/NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505
Issue of Publication
Research Tools and Approaches: Cancer Research Methods
Journal of Biological Chemistry
Page last reviewed: March 11, 2019
Content source: National Institute for Occupational Safety and Health Education and Information Division