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

• Published in: Molecular and cellular biochemistry 2004-01, Vol.255 (1-2), p.93-101
• Main Authors: Joseph, Pius, Lei, Yi-Xiong, Ong, Tong-man
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Cadmium; Cadmium - metabolism; Cadmium - toxicity; Carcinogenesis; Cell Transformation, Neoplastic - chemically induced; Cell Transformation, Neoplastic - genetics; DNA, Complementary; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Mice; Mice, Nude; Molecular Sequence Data; Peptide Elongation Factor 1 - genetics; Peptide Elongation Factor 1 - metabolism; Prokaryotic Initiation Factor-3 - genetics; Prokaryotic Initiation Factor-3 - metabolism; Proteins; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Up-Regulation - drug effects
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1023/B:MCBI.0000007265.38475.f7

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.