Eukaryotic translation initiation factor 4E is a cellular target for toxicity and death due to exposure to cadmium chloride

被引:54
作者
Othumpangat, S
Kashon, M
Joseph, P
机构
[1] NIOSH, Mol Carcinogenesis Lab, Toxicol & Mol Biol Branch, CDC, Morgantown, WV 26505 USA
[2] NIOSH, Biostat & Epidemiol Branch, Hlth Effects Lab Div, Morgantown, WV 26505 USA
关键词
D O I
10.1074/jbc.M414303200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:25162 / 25169
页数:8
相关论文
共 46 条
[1]   Cadmium induces c-myc, p53, and c-jun expression in normal human prostate epithelial cells as a prelude to apoptosis [J].
Achanzar, WE ;
Achanzar, KB ;
Lewis, JG ;
Webber, MM ;
Waalkes, MP .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 2000, 164 (03) :291-300
[2]  
Alam J, 2000, J BIOL CHEM, V275, P27694
[3]  
ALTMANN M, 1989, J BIOL CHEM, V264, P12145
[4]  
AYLETT BJ, 1979, CHEM BIOCH BIOL CADM
[5]  
Berkel HJ, 2001, CANCER EPIDEM BIOMAR, V10, P663
[6]   Cadmium, gene regulation, and cellular signalling in mammalian cells [J].
Beyersmann, D ;
Hechtenberg, S .
TOXICOLOGY AND APPLIED PHARMACOLOGY, 1997, 144 (02) :247-261
[7]   eIF-4E expression and its role in malignancies and metastases [J].
De Benedetti, A ;
Graff, JR .
ONCOGENE, 2004, 23 (18) :3189-3199
[8]   eIF4E expression in tumors: its possible role in progression of malignancies [J].
De Benedetti, A ;
Harris, AL .
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 1999, 31 (01) :59-72
[9]   EXPRESSION OF ANTISENSE RNA AGAINST INITIATION-FACTOR EIF-4E MESSENGER-RNA IN HELA-CELLS RESULTS IN LENGTHENED CELL-DIVISION TIMES, DIMINISHED TRANSLATION RATES, AND REDUCED LEVELS OF BOTH EIF-4E AND THE P220 COMPONENT OF EIF-4F [J].
DEBENEDETTI, A ;
JOSHIBARVE, S ;
RINKERSCHAEFFER, C ;
RHOADS, RE .
MOLECULAR AND CELLULAR BIOLOGY, 1991, 11 (11) :5435-5445
[10]   Disruption of the intracellular sulfhydryl homeostasis by cadmium-induced oxidative stress leads to protein thiolation and ubiquitination in neuronal cells [J].
Figueiredo-Pereira, ME ;
Yakushin, S ;
Cohen, G .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (21) :12703-12709