Metal-responsive transcription factor 1 (MTF-1) specifically binds to metal response elements (MREs) associated with a number of metal- and stress-responsive genes. Human MTF-1 contains a cysteine-rich cluster, -632Cys-Gln-Cys-Gln-Cys-Ala-Cys638-, conserved from pufferfish to humans far removed from the MRE-binding zinc finger domain and just C-terminal to a previously mapped serine/threonine-rich transcriptional activation domain. MTF-1 proteins containing two Cys→Ala substitutions (C632A/C634A) or a deletion in this region altogether (Δ(632-644)) are significantly impaired in their ability to induce Zn(II)- and Cd(II)-responsive transcription of a MRE-linked reporter gene in transiently transfected mouse dko7 (MTF-1-/-) cells in culture under moderate metal stress but retain the ability to drive basal levels of transcription in a MRE-dependent manner in vivo and in vitro. In addition, the mutated proteins respond to induction by Zn(II) or Cd(II) with nuclear translocation and MRE binding activities comparable with wild-type MTF-1. Attempts to rescue the Δ(632-644) deletion mutant phenotype by inserting similar Cys-rich sequences from Drosophila MTF-1 were unsuccessful, suggesting that the structure of this motif within intact human MTF-1, rather than the simple presence of multiple closely spaced Cys residues, is required for function. This cysteine cluster therefore functions at a step subsequent to nuclear translocation and MRE-binding DNA to naked promoter-containing DNA and appears to be specifically required for MTF-1 to activate transcription in the presence of inducing heavy metal ions. Metal-responsive transcription factor 1 (MTF-1) specifically binds to metal response elements (MREs) associated with a number of metal- and stress-responsive genes. Human MTF-1 contains a cysteine-rich cluster, -632Cys-Gln-Cys-Gln-Cys-Ala-Cys638-, conserved from pufferfish to humans far removed from the MRE-binding zinc finger domain and just C-terminal to a previously mapped serine/threonine-rich transcriptional activation domain. MTF-1 proteins containing two Cys→Ala substitutions (C632A/C634A) or a deletion in this region altogether (Δ(632-644)) are significantly impaired in their ability to induce Zn(II)- and Cd(II)-responsive transcription of a MRE-linked reporter gene in transiently transfected mouse dko7 (MTF-1-/-) cells in culture under moderate metal stress but retain the ability to drive basal levels of transcription in a MRE-dependent manner in vivo and in vitro. In addition, the mutated proteins respond to induction by Zn(II) or Cd(II) with nuclear translocation and MRE binding activities comparable with wild-type MTF-1. Attempts to rescue the Δ(632-644) deletion mutant phenotype by inserting similar Cys-rich sequences from Drosophila MTF-1 were unsuccessful, suggesting that the structure of this motif within intact human MTF-1, rather than the simple presence of multiple closely spaced Cys residues, is required for function. This cysteine cluster therefore functions at a step subsequent to nuclear translocation and MRE-binding DNA to naked promoter-containing DNA and appears to be specifically required for MTF-1 to activate transcription in the presence of inducing heavy metal ions. Zinc and other transition metal ions play diverse roles in many biological processes, serving as structural components of proteins (1Laity J.H. Lee B.M. Wright P.E. Curr. Opin. Struct. Biol. 2001; 11: 39-46Crossref PubMed Scopus (1074) Google Scholar) or as essential cofactors in enzyme-catalyzed reactions (2Coleman J.E. Curr. Opin. Chem. Biol. 1998; 2: 222-234Crossref PubMed Scopus (329) Google Scholar, 3McCall K.A. Huang C. Fierke C.A. J. Nutr. 2000; 130: 1437S-1446SCrossref PubMed Google Scholar). However, all metal ions become cytotoxic at high intracellular concentrations. Metal-responsive control of gene expression allows organisms to regulate the available concentration of beneficial metal ions such as zinc, copper, and iron within an acceptable range while removing toxic heavy metals that play no biological function such as cadmium, lead, mercury, and arsenic. Metal-responsive transcription factor 1 (MTF-1) 1The abbreviations used are: MTF-1metal-responsive transcription factor 1MREmetal response elementDMEDulbecco's modified Eagle's mediumFBSfetal bovine serumHEKhuman embryonic kidneyDTTdithiothreitolFfingerZFzinc fingerTricineN-[2-hydroxy-1,1-bis(hydroxymethyl)ethyl]glycine. was identified as a protein in higher eukaryotes that specifically binds to metal response element (MRE) DNA sequences associated with the genes encoding metallothioneins (4Stuart G.W. Searle P.F. Chen H.Y. Brinster R.L. Palmiter R.D. Proc. Natl. Acad. Sci. U. S. A. 1984; 81: 7318-7322Crossref PubMed Scopus (247) Google Scholar, 5Culotta V.C. Hamer D.H. Mol. Cell. Biol. 1989; 9: 1376-1380Crossref PubMed Scopus (161) Google Scholar, 6Westin G. Schaffner W. EMBO J. 1988; 7: 3763-3770Crossref PubMed Scopus (231) Google Scholar, 7Radtke F. Heuchel R. Georgiev O. Hergersberg M. Gariglio M. Dembic Z. Schaffner W. EMBO J. 1993; 12: 1355-1362Crossref PubMed Scopus (338) Google Scholar), a family of conserved cysteine-rich, metal-chelating proteins (8Vasak M. Hasler D.W. Curr. Opin. Chem. Biol. 2000; 4: 177-183Crossref PubMed Scopus (371) Google Scholar). MRE sequences and MTF-1 are required for both basal and metal-inducible metallothionein gene transcription (9Heuchel R. Radtke F. Georgiev O. Stark G. Aguet M. Schaffner W. EMBO J. 1994; 13: 2870-2875Crossref PubMed Scopus (406) Google Scholar). 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PubMed Scopus Google Scholar) in transcription of human MTF-1 is by the MTF-1 expression were with reporter contains MRE sequences just of a basal transcription of control for also the in transcription of is by the were with the wild-type MTF-1 expression expression of the reporter gene of transfected cells with Zn(II) or Cd(II) in and induction of levels of expression were from the of activities of and in of transfected This was to 1 for the with the wild-type at a concentration of in the of metal for with or with metal at were in of of expression under is the levels of metal the cells were that to heavy metals this of zinc J. Biol. Chem. 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In that expression in the of metal induction was expression for the or Δ(632-644) were used in of wild-type MTF-1 but that this was this was the presence of the MRE in the reporter were at a concentration of MTF-1 expression of to basal the of were also with wild-type MTF-1 at a concentration of used in the in and the expression levels in were to the under expression a of and the presence of the MRE in the reporter In the expression levels were with the and Δ(632-644) MTF-1 to that with wild-type MTF-1, expression with all MTF-1 was the presence of the MRE in the reporter the and Δ(632-644) were to basal levels of transcription within a factor of of wild-type MTF-1, but were far in their transcriptional response to metal induction MRE by MTF-1 of basal transcription by the MTF-1 and Δ(632-644) that both of specifically the this of dko7 cells transiently transfected with the expression as a of MTF-1, and a containing a of a MRE F. Heuchel R. Georgiev O. Hergersberg M. Gariglio M. 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