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Eukaryotic translation initiation factor 4E is a cellular target for toxicity and death due to exposure to cadmium
Sreekumar Othumpangat1, Michael Kashon, Pius Joseph
1Molecular Carcinogenesis Laboratory, Toxicology and Molecular Biology Branch, Biostatistics and Epidemiology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA.
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.
Insights
Cadmium exposure causes cell death by degrading translation initiation factor 4E (eIF4E), a key protein. Reducing eIF4E levels leads to cytotoxicity, while increasing it offers protection against cadmium toxicity.
Area of Science:
- Molecular Biology
- Cell Biology
- Toxicology
Background:
- Translation initiation factor 4E (eIF4E) is crucial for protein synthesis and cell growth.
- Cadmium is a known human carcinogen that induces cytotoxicity and cell death.
- The precise mechanisms by which cadmium affects eIF4E and leads to cell death are not fully understood.
Purpose of the Study:
- To investigate whether eIF4E is a target for cadmium-induced cytotoxicity and cell death.
- To elucidate the molecular mechanisms underlying cadmium's effect on eIF4E.
- To determine the role of eIF4E levels in cellular response to cadmium exposure.
Main Methods:
- Exposure of human cell lines (HCT15, PLC/PR/5, HeLa, Chang) to cadmium chloride.
- Gene silencing of eIF4E using small interfering RNA (siRNA).
- Overexpression of the eIF4E gene.
- Analysis of eIF4E protein and mRNA levels, ubiquitination, and proteasome activity.
- Assessment of cyclin D1 protein levels.
Main Results:
- Cadmium exposure significantly decreased eIF4E protein levels, leading to cytotoxicity and cell death.
- Specific silencing of eIF4E expression mimicked cadmium's cytotoxic effects.
- Overexpression of eIF4E conferred protection against cadmium-induced cell death.
- Cadmium enhanced eIF4E ubiquitination and proteasomal degradation, without altering eIF4E mRNA levels.
- Both cadmium exposure and eIF4E silencing reduced cyclin D1 levels, suggesting eIF4E's role in its regulation.
Conclusions:
- Cadmium chloride induces cytotoxicity and cell death by promoting eIF4E ubiquitination and proteolysis.
- Decreased eIF4E levels contribute to cadmium-induced cell death and reduced cyclin D1 expression.
- eIF4E is a critical target in cadmium-induced cellular toxicity and carcinogenicity.
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