CADMIUM, GENE-REGULATION, AND CELLULAR SIGNALING IN MAMMALIAN-CELLS

Effects of the carcinogenic metal cadmium on the regulation of mammali an gene expression are reviewed and discussed in the light of observat ions on interference with cellular signal transduction pathways. Cadmi um ions are taken up through calcium channels of the plasma membrane o f various tell types, and cadmium is accumulated intracellularly due t o its binding to cytoplasmic and nuclear material. At elevated cytotox ic concentrations, cadmium inhibits the biosyntheses of DNA, RNA, and protein, and it induces lipid peroxidation, DNA strand breaks, and chr omosome aberrations. Cadmium compounds as such are only weak mutagens and clastogens. However, cadmium at noncytotoxic doses interferes with DNA repair processes and enhances the genotoxicity of directly acting mutagens. Hence, the inhibition of repair and detoxifying enzymes by this metal may partially explain the observed weak genotoxic propertie s of this metal. Nongenotoxic mechanisms upregulating intracellular si gnalling pathways leading to increased mitogenesis are discussed as ma jor mechanisms for the interpretation of the carcinogenic activity by chronic cadmium exposure. About 1 mu M cadmium stimulates DNA synthesi s and cell proliferation in various cell lines, whereas more elevated concentrations are inhibitory. Cadmium enhances the expression of seve ral classes of genes at concentrations of a few mu M. It stimulates th e expression of immediate early genes (c-fos, c-jun, and c-myc), of th e tumor suppressor gene p53, and of genes coding for the syntheses of protective molecules, including metallothioneins, glutathione, and str ess (heat shock) proteins. The mechanisms underlying the modulation of gene activity by cadmium are discussed in terms of interference with cellular signalling at the levels of cell surface receptors, cellular calcium and zinc homeostases, protein phosphorylation, and modificatio n of transcription factors. In considering the available evidence, the carcinogenic properties of cadmium are interpreted using a multifacto rial approach involving indirect genotoxicity (interference with DNA r epair) and the upregulation of mitogenic signalling pathways. (C) 1997 Academic Press.