Metals and cellular signaling in mammalian cells

A number of heavy metals are known to be essential for life, but most of these can also be toxic to cells under certain circumstances, or at elevated levels. Metals can directly induce gene expression through the actions of metal-responsive transcription factors. However, metals can also influence the response to non-metal extracellular signals. Cells respond to extracellular signals through a variety of different, but often interacting, signal transduction pathways. Metals can alter cell behaviour by interacting with transcription factors and transduction molecules, many of which are dependent on metals (primarily zinc) for their action. In addition, metals can affect cells in more nonspecific ways, for example, by inducing a generalized stress response or by cross-linking cell surface thiol groups. The prominent role of zinc in signal transduction combined with low intracellular free zinc levels has lead to the speculation that cellular signaling and gene expression may be regulated, in part, by zinc bioavailability. Experimental modification of the levels of the intracellular metal-binding protein, metallothionein (MT), results in altered responsiveness to extracellular signals. This observation suggests that MT is capable of influencing gene expression, perhaps by regulating the level of intracellular free zinc.