Cadmium, gene regulation, and cellular signalling in mammalian cells.

Effects of the carcinogenic metal cadmium on the regulation of mammalian gene expression are reviewed and discussed in the light of observations on interference with cellular signal transduction pathways. Cadmium ions are taken up through calcium channels of the plasma membrane of various cell types, and cadmium is accumulated intracellularly due to its binding to cytoplasmic and nuclear material. At elevated cytotoxic concentrations, cadmium inhibits the biosyntheses of DNA, RNA, and protein, and it induces lipid peroxidation, DNA strand breaks, and chromosome 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 properties of this metal. Nongenotoxic mechanisms upregulating intracellular signalling pathways leading to increased mitogenesis are discussed as major mechanisms for the interpretation of the carcinogenic activity by chronic cadmium exposure. About 1 microM cadmium stimulates DNA synthesis and cell proliferation in various cell lines, whereas more elevated concentrations are inhibitory. Cadmium enhances the expression of several classes of genes at concentrations of a few microM. It stimulates the expression of immediate early genes (c-fos, c-jun, and c-myc), of the tumor suppressor gene p53, and of genes coding for the syntheses of protective molecules, including metallothioneins, glutathione, and stress (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 modification of transcription factors. In considering the available evidence, the carcinogenic properties of cadmium are interpreted using a multifactorial approach involving indirect genotoxicity (interference with DNA repair) and the upregulation of mitogenic signalling pathways.