The Drosophila homolog of mammalian zinc finger factor MTF-1 activates transcription in response to heavy metals

Metallothioneins (MTs) are short, cysteine-rich proteins for heavy metal ho meostasis and detoxification; they bind a variety of heavy metals and also act as radical scavengers. Transcription of mammalian MT genes is activated by heavy metal load via the metal-responsive transcription factor 1 (MTF-1 ), an essential zinc finger protein whose elimination in mice leads to embr yonic lethality due to liver decay. Here we characterize the Drosophila hom olog of vertebrate MTF-1 (dMTF-1), a 791-amino-acid protein which is most s imilar to its mammalian counterpart in the DNA-binding zinc finger region. Like mammalian MTF-1, dMTF-1 binds to conserved metal-responsive promoter e lements (MREs) and requires zinc for DNA binding, yet some aspects of heavy metal regulation have also been subject to divergent evolution between Dro sophila and mammals. dMTF-1, unlike mammalian MTF-1, is resistant to low pH (6 to 6.5). Furthermore, mammalian MT genes are activated best by zinc and cadmium, whereas in Drosophila cells, cadmium and copper are more potent i nducers than zinc. The latter species difference is most likely due to aspe cts of heavy metal metabolism other than MTF-1, since in transfected mammal ian cells, dMTF-1 responds to zinc like mammalian MTF-1. Heavy metal induct ion of both Drosophila MTs is abolished by double-stranded RNA interference : small amounts of cotransfected double-stranded RNA of dMTF-1 but not of u nrelated control RNA inhibit the response to both the endogenous dMTF-1 and transfected dMTF-1. These data underline an important role for dMTF-1 in M T gene regulation and thus heavy metal homeostasis.