Regulation of metallothionein gene transcription - Identification of upstream regulatory elements and transcription factors responsible for cell-specific expression of the metallothionein genes from Caenorhabditis elegans

Metallothioneins are small, cysteine-rich proteins that function in metal d etoxification and homeostasis. Metallothionein transcription is controlled by cell-specific factors, as well as developmentally modulated and metal-re sponsive pathways. By using the nematode Caenorhabditis elegans as a model system, the mechanism that controls cell-specific metallothionein transcrip tion in vivo was investigated. The inducible expression of the C. elegans m etallothionein genes, mtl-1 and mtl-2, occurs exclusively in intestinal cel ls. Sequence comparisons of these genes with other C. elegans intestinal ce ll-specific genes identified multiple repeats of GATA transcription factor- binding sites (i.e. GATA elements). In vivo deletion and site-directed muta tion analyses confirm that one GATA element in mtl-1 and two in mtl-2 are r equired for transcription. Electrophoretic mobility shift assays show that the C, elegans GATA transcription factor ELT-2 specifically binds to these elements. Ectopic expression of ELT-S in non-intestinal cells of C. elegans activates mtl-2 transcription in these cells. Likewise, mtl-2 is not expre ssed in nematodes in which elt-2 has been disrupted. These results indicate that cell-specific transcription of the C. elegans metallothionein Genes i s regulated by the binding of ELT-S to GATA elements in these promoters. Fu rthermore, a model is proposed where ELT-S constitutively activates metallo thionein expression; however, a second metal-responsive factor prevents tra nscription in the absence of metals.