EFFECTS OF CADMIUM ON NUCLEAR-PROTEIN KINASE-C

Cadmium is a carcinogen whose genotoxicity is only weak. Besides its t umor-initiating capacity, cadmium may be tumor-promoting since it inte rferes with several steps of cellular signal transduction. We have inv estigated effects of cadmium(II) on protein kinase C (PKC), which is a key enzyme in the control of cellular growth and differentiation. Tum or-promoting phorbol esters cause an activation and translocation of P KC from the cytosol to the plasma membrane and to the nucleus of mamma lian cells. In mouse 3T3/10 T 1/2 fibroblasts, cadmium(II) potentiated the effect of phorbol ester on nuclear binding and activation of PKC. Furthermore, in a reconstituted system consisting of rat liver nuclei and rat brain PKC, cadmium stimulated the binding of the enzyme to a 105-kDa protein. We propose a model in which cadmium(II) substitutes f or zinc(II) in the regulatory domain of PKC, thus rendering the putati ve protein-protein binding site exposed. Further work is required to e lucidate the potential role of the nuclear PKC binding protein(s) in t he control of cell proliferation.