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J.Health Sci., 55(4), 484-494, 2009
-Review-
Mechanisms of Heavy Metal Sensing by Metal Response Element-binding Transcription Factor-1
Tomoki Kimura,*, a Norio Itoh,b
and Glen K. Andrewsc
aDepartment of Toxicology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan,
bDepartment of Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan and
cDepartment of Biochemistry and Molecular Biology, University of Kansas Medical Center, 39th and Rainbow Blvd., Kansas City, Kansas, 66160-7421, U.S.A.
Heavy metal homeostasis and detoxification systems are often regulated by changes in gene transcription. In higher eukaryotes, metal response element (MRE)-binding transcription factor-1 (MTF-1) is the only known metal-sensing transcription factor and zinc is the only heavy metal which can reversibly and directly activate the DNA-binding activity of MTF-1, leading to its nuclear retention, promoter binding and induction or repression of transcription. Although, cadmium, copper and oxidative stresses can cause the activation of the DNA-binding activity of MTF-1 in vivo, they apparently do so, at least in part, by causing the redistribution of intracellular zinc. MTF-1-dependent metal-sensing transcription mechanisms are not fully understood but clearly involve zinc binding to its unique zinc finger domain. Recently, zinc has been shown to induce the formation of a co-activator complex containing MTF-1 and the histone acetyltransferase p300 which plays an essential role in the activation of mouse metallothionein-I (MT-I) gene transcription. In this review, we focus on current understanding of the mechanisms by which MTF-1 senses heavy metals and activates gene expression.
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