Molecular cloning and functional analysis of a novel cadmium-responsive proto-oncogene.
The molecular mechanisms potentially responsible for cell transformation and tumorigenesis induced by cadmium, a human carcinogen, were investigated by differential gene expression analysis of BALB/c-3T3 cells transformed with cadmium chloride (CdCl(2)). Differential display analysis of gene expression revealed consistent overexpression of mouse translation initiation factor 3 (TIF3; GenBank accession number AF271072) in the cells transformed with CdCl(2) when compared with nontransformed cells. The predicted protein encoded by TIF3 cDNA exhibited 99% similarity to human eukaryotic initiation factor 3 p36 protein. A M(r) 36,000 protein was detected in cells transfected with an expression vector containing TIF3 cDNA. Transfection of NIH3T3 cells with an expression vector containing TIF3 cDNA resulted in overexpression of the encoded protein, and this was associated with cell transformation, as evidenced by the appearance of transformed foci exhibiting anchorage-independent growth on soft agar and tumorigenic potential in nude mice. Expression of the antisense RNA against TIF3 mRNA resulted in significant reversal of oncogenic potential of the CdCl(2)-transformed BALB/c-3T3 cells. Taken together, these findings demonstrate for the first time that the cell transformation and tumorigenesis induced by CdCl(2) are due, at least in part, to the overexpression of TIF3, a novel cadmium-responsive proto-oncogene.
Joseph
Pius
P
Molecular Epidemiology Laboratory, Toxicology and Molecular Biology Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505, USA. pcj5@cdc.gov
Lei
Yi-Xiong
YX
Whong
Wen-Zong
WZ
Ong
Tong-man
TM
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D019256:Cadmium Chloride / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics; D039642:Eukaryotic Initiation Factors; D005656:Fungal Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D015870:Gene Expression; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010448:Peptide Initiation Factors; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000187:drug effects* / Q000502:physiology; D012316:RNA Nucleotidyltransferases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D016372:RNA, Antisense / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins; D014162:Transfection
D002273:Carcinogens; D018076:DNA, Complementary; D039642:Eukaryotic Initiation Factors; D005656:Fungal Proteins; C000715470:MAS1 protein, human; D010448:Peptide Initiation Factors; D000090063:Proto-Oncogene Mas; D016372:RNA, Antisense; D029701:Saccharomyces cerevisiae Proteins; C083432:TIF3 protein, S cerevisiae; D012316:RNA Nucleotidyltransferases; D019256:Cadmium Chloride