Up-regulation of expression of translation factors - a novel molecular mechanism for cadmium carcinogenesis

The molecular mechanisms potentially responsible for cadmium carcinogenesis were investigated by differential gene expression analysis of Balb/ c- 3T3 cells morphologically transformed with cadmium chloride. Differential display analysis of gene expression revealed overexpression of mouse Translation Initiation Factor 3 ( TIF3; GenBank Accession Number AF 271072) and Translation Elongation Factor- 1delta ( TEF- 1delta; GenBank Accession Number AF 304351) in the transformed cells compared with the control cells. The full length cDNAs for TIF3 and TEF- 1delta were cloned and sequenced. Transfection of mammalian cells with an expression vector containing either TIF3 or TEF- 1delta cDNA resulted in overexpression of the encoded protein. Overexpression of the cDNA- encoded TIF3 and TEF- 1delta proteins in NIH3T3 cells was oncogenic as evidenced by the appearance of transformed foci capable of anchorage- independent growth on soft agar and tumorigenesis in nude mouse. Blocking the translation of TIF3 and TEF- 1delta proteins using the corresponding antisense mRNA resulted in a significant reversal of the oncogenic potential of cadmium transformed Balb/ c- 3T3 cells as evidenced from the suppression of anchorage- independent growth on soft agar and diminished tumorigenesis in nude mouse. These findings demonstrate that the up- regulation of expression of TIF3 and TEF- 1delta is a novel molecular mechanism responsible, at least in part, for cadmium carcinogenesis.