Abstract
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.
Highlights
Cadmium, a highly toxic chemical and one of the members of the U.S Environmental Protection Agency’s “Priority List of Chemicals,” has been classified by the International Agency for Research on Cancer as a human carcinogen
Multiple genes, including those involved in several critical cellular functions, have been identified as potential targets for cadmium-induced cytotoxicity and cell death; the one or more precise mechanisms that lead to their deregulation of expression in response to cadmium exposure as well as the functional significance of such alterations with respect to cadmium toxicity are not well studied
We have investigated the effect of cadmium exposure on the cellular expression level of eukaryotic translation initiation factor 4E (eIF4E), the rate-limiting translation initiation factor involved in eukaryotic protein synthesis
Summary
Vol 280, No 26, Issue of July 1, pp. 25162–25169, 2005 Printed in U.S.A. Eukaryotic Translation Initiation Factor 4E Is a Cellular Target for Toxicity and Death Due to Exposure to Cadmium Chloride*. 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. Multiple genes, including those involved in several critical cellular functions, have been identified as potential targets for cadmium-induced cytotoxicity and cell death (reviewed in Ref. 9); the one or more precise mechanisms that lead to their deregulation of expression in response to cadmium exposure as well as the functional significance of such alterations with respect to cadmium toxicity are not well studied. We have investigated the effect of cadmium exposure on the cellular expression level of eIF4E, the rate-limiting translation initiation factor involved in eukaryotic protein synthesis. The underlying mechanisms responsible for cadmium-induced deregulation of eIF4E leading to cytotoxicity and cell death are presented
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