Antisense oligonucleotide of c-myc discriminates between zinc- and dexamethasone-induced synthesis of metallothionein.

The metallothionein II genes, whose structures are highly conserved throughout the animal kingdom, are composed of three exons and two introns. By using synthetic oligonucleotides with sequences complementary to the mRNA coding for human metallothionein II, we have shown that (a) inhibition of metallothionein synthesis causes cells to die from metal toxicity, (b) metallothionein possesses an essential gene, and (c) modifications in oligonucleotide structures exhibit specificity in inhibiting metallothionein synthesis. Furthermore, we have prepared a synthetic antisense oligodeoxyribonucleotide to the mRNA specific for human c-myc and tested its potential to regulate metallothionein synthesis in Chang liver cells in culture. The results of this study revealed that the c-myc antisense oligodeoxyribonucleotide led to greater induction of zinc-promoted but not of cadmium- or dexamethasone-induced synthesis of metallothionein. These data are interpreted to suggest that c-myc acts as a repressor of at least one of the six human metallothionein isoforms and demonstrates a unique mode of regulation capable of discriminating between zinc- and dexamethasone-induced synthesis of metallothionein.