Metals and cellular signaling in mammalian cells

A number of heavy metals are known to be essential for life, but most of th ese can also be toxic to cells under certain circumstances, or at elevated levels. Metals can directly induce gene expression through the actions of m etal-responsive transcription factors. However, metals can also influence t he response to non-metal extracellular signals. Cells respond to extracellu lar signals through a variety of different, but often interacting, signal t ransduction pathways. Metals can alter cell behaviour by interacting with t ranscription factors and transduction molecules, many of which are dependen t on metals (primarily zinc) for their action. In addition, metals can affe ct cells in more nonspecific ways, for example, by inducing a generalized s tress response or by cross-linking cell surface thiol groups. The prominent role of zinc in signal transduction combined with low intracellular free z inc levels has lead to the speculation that cellular signaling and gene exp ression may be regulated, in part, by zinc bioavailability. Experimental mo dification of the levels of the intracellular metal-binding protein, metall othionein (MT), results in altered responsiveness to extracellular signals. This observation suggests that MT is capable of influencing gene expressio n, perhaps by regulating the level of intracellular free zinc.