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.