CADMIUM(II) SPECIFICALLY INTERACTS WITH CELLULAR SIGNALING TO INDUCE PROTOONCOGENES C-FOS AND C-JUN IN RAT PC12 CELLS

Cadmium(II) compounds are carcinogens but only weakly mutagens. Becaus e Cd(II) at low micromolar concentrations stimulates cell growth and i nduces some proto-oncogenes with several mammalian cell lines, the sti mulation of cell proliferation is discussed as a major mechanism of th e carcinogenicity of this metal. In the present work, the induction of the cellular proto-oncogenes c-fos and c-jun by Cd(II) was studied in rat PC12 cells. Several cellular signal transduction elements were te sted as mediators of the proto-oncogene induction by cadmium. Cd(II) d oes not evoke mobilization of free intracellular Ca2+ in PC12 cells, a nd there was no impair ment of the effect of Cd(II) by inhibitors of p rotein kinase A or of MAPK kinase. However, bisindolylmaleimide I, a s pecific inhibitor of protein kinase C abolished the protooncogene indu ction by Cd(II). Hence, a critical role for protein kinase C in the mi togenic effect of Cd(II) is inferred, and a substitution of structural Zn2+ ions by Cd2+ ions in this enzyme is discussed as the putative me chanism.