Regulation of metallothionein gene expression

The metallothioneins are small, cysteine-rich proteins that have the capacity for high affinity binding of heavy metal ions, and whose synthesis is regulated by metal ion concentrations. These properties suggest that they play pivotal roles in the metabolism of the relatively nontoxic essential metals (zinc and copper), as well as toxic heavy metals (cadmium), a concept supported by a variety of studies of cells in culture, as well as in intact animals. Expression of the metallothionein genes may have important implications in the nutritional status of the animal, in its response to stresses (inflammation, heavy metal toxicity), and in embryonic, fetal and neonatal development. The complementary DNAs and genes that encode the metallothioneins have been cloned and analyzed from a wide variety of eukaryotes. Striking features of the metallothioneins include: their high degree of amino acid sequence similarity (including conservation in the placement of cysteine residues in the molecule reflecting their function in metal binding); a conserved tripartite gene structure; and their transcriptional induction by metal ions, as well as other hormonal and environmental stimuli. The precise mechanisms and biochemical pathways by which cells transduce environmental signals into transcriptional induction of the metallothionein genes are beginning to be defined. Recent studies indicate that metal effects are exerted via positive trans-acting factors induced to interact with cis-acting DNA sequences in the promoter, in turn leading to transcriptional induction. However, the metallothionein gene promoter is structurally complex, and contains binding sites for a variety of nuclear proteins that likely regulate basal as well as induced levels of expression of these genes. Recent studies also suggest the possible involvement of post-transcriptional processes in the regulation of metallothionein levels in the cell. Furthermore, evidence of striking differences in the levels of metallothionein gene expression among various cell types in vivo have recently been documented. Although several detailed reviews of the metallothioneins have been published recently, this review will focus, in large part, on the molecular biology of the metallothioneins, with particular emphasis on recent advances in our understanding of the mechanisms regulating expression of these interesting and important genes. Given the large volume of literature on the metallothioneins and the space limitations of this review, it is impossible to comprehensively cite the studies of each of my colleagues who have contributed so much to this field. Instead the reader is often directed to reviews of this subject for much of the earlier literature, and emphasis is placed on more current publications in this field.