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J. Biol. Chem., Vol. 279, Issue 6, 4515-4522, February 6, 2004

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A Novel Cysteine Cluster in Human Metal-responsive Transcription Factor 1 Is Required for Heavy Metal-induced Transcriptional Activation in Vivo^*

Xiaohua Chen, Bo Zhang, Philip M. Harmon, Walter Schaffner¶, David O. Peterson, and David P. Giedroc¶

From the Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128 and Institut für Molekularbiologie, Universität Zürich, Winterhurer Strasse 190, CH-8057, Zürich, Switzerland

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 CysAla substitutions (C632A/C634A) or a deletion in this region altogether ((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 (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.

Received for publication, August 12, 2003 , and in revised form, October 30, 2003.

^* This work was supported by grants from the National Institutes of Health (GM042569) and Robert F. Welch Foundation (A-1275) (to D. P. G.) and from the Schweizerischer Nationalfonds and the Kanton Zürich (to W. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence may be addressed. Tel.: 979-845-4231; Fax: 979-845-4946; E-mail: giedroc{at}tamu.edu (D. P. G.) or Tel.: 41-1-623-3151; Fax: 41-1-635-6811; E-mail: walter.schaffner{at}molbio.unizh.ch.

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