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A more recent version of this article appeared on February 6, 2004
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M308924200v1
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Papers In Press, published online ahead of print November 10, 2003
J. Biol. Chem, 10.1074/jbc.M308924200
Submitted on August 12, 2003
Revised on October 30, 2003
Accepted on November 10, 2003

A novel cysteine cluster in human MTF-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

Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843-2128

Corresponding Author: giedroc{at}tamu.edu

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 ((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 they 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 to 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 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.


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