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J. Biol. Chem., Vol. 280, Issue 26, 25162-25169, July 1, 2005

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Eukaryotic Translation Initiation Factor 4E Is a Cellular Target for Toxicity and Death Due to Exposure to Cadmium Chloride^*

Sreekumar Othumpangat, Michael Kashon, and Pius Joseph¶

From the Molecular Carcinogenesis Laboratory, Toxicology and Molecular Biology Branch, Biostatistics and Epidemiology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health (NIOSH), Morgantown, West Virginia 26505

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.

Received for publication, December 20, 2004 , and in revised form, May 3, 2005.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: MS 3014, Molecular Carcinogenesis Laboratory, Toxicology and Molecular Biology Branch, CDC/NIOSH, 1095 Willowdale Rd., Morgantown, WV 26505. Tel.: 304-285-6240; Fax: 304-285-5708; E-mail: pcj5{at}cdc.gov.

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