Original MRE-binding Transcriptional Factor Gene in Normal Humans is ZRF, not MTF-1.

Kita, Kenji; Miura, Nobuhiko; Yoshida, Minoru; Matsubara, Mitsunobu; Imai, Yutaka; Naganuma, Akira

doi:10.1248/jhs.47.587

Cited by 3 publications

(1 citation statement)

References 25 publications

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“…The main transcription factor involved in the regulation of expression of the gene for MT-IIA is metal transcription factor-1 (MTF-1) (Kita et al 2001;Otsuka et al 1994;Westin and SchaVner 1988). This factor is activated by Zn and by Cd and it binds to the consensus sequence (TGCRCNC) of the metal-responsive element (MRE) within the promoter of the gene for MT-IIA gene, thereby promoting transcription of this gene (Carter et al 1984;Karin et al 1984;Stuart et al 1985).…”

Section: Resultsmentioning

confidence: 99%

Potential effect on cellular response to cadmium of a single-nucleotide A → G polymorphism in the promoter of the human gene for metallothionein IIA

et al. 2006

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Most people generally ingest cadmium in their food. Cadmium that has accumulated in tissues induces the synthesis of metallothioneins (MTs) which are metal-binding proteins that bind tightly to cadmium to inhibit its renal toxicity. Individuals whose ability to induce the synthesis of MTs is low seem likely to be particularly susceptible to the toxic effects of cadmium. In this study, we analyzed the polymorphism of the promoter region of the gene for MT-IIA, the major species of MT in humans, in 119 adult Japanese subjects. We found that about 18% of the subjects had an A --> G single-nucleotide polymorphism in the core region of the promoter near the TATA box. A reporter-gene assay using HEK293 cells showed that replacement of A by G at position -5 reduced the efficiency of the cadmium-induced transcription of the gene for MT-IIA. This single-nucleotide polymorphism inhibited the binding of nuclear proteins to the core promoter region of the gene for MT-IIA. When the promoter region upstream of the TATA box was replaced by a sequence that contained three dioxin-responsive elements, the reporter-gene assay demonstrated that the A --> G single-nucleotide polymorphism resulted in a marked reduction in the rate of dioxin-induced transcription. These results suggest that the A --> G single-nucleotide polymorphism reduces the efficiency of those aspects of the transcription of the gene for MT-IIA that are controlled by general transcription factors.

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Section: Resultsmentioning

confidence: 99%

Potential effect on cellular response to cadmium of a single-nucleotide A → G polymorphism in the promoter of the human gene for metallothionein IIA

et al. 2006

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Mechanism of Metallothionein Gene Activation Mediated by Heavy-metal Dependent Transcription Factor MTF-1

Otsuka

Ohno²,

Suzuki³

et al. 2007

YAKUGAKU ZASSHI

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Transcriptional activation of metallothionein (MT) genes by heavy metals is a valuable system for understanding the functions of MT as well as the cellular response against heavy metals. Although it is now known that heavy metal signals culminating in MT induction converge upon a transcription factor MTF-1, the mechanism underlying the MTF-1 response to heavy metals has not been elucidated. To address this issue, we investigated various aspects of the in vivo response of MTF-1 against heavy metals. Chromatin immunoprecipitation assay showed that heavy metal-dependent DNA binding of MTF-1 is the critical step in vivo. MTF-1 is primarily localized in the nucleus so that heavy metal-dependent nuclear translocation demonstrated by other groups does not seem to be universal and hence may not be critical for activation of MTF-1. In the six Znˆnger motifs, the hallmark of MTF-1, the third and the fourthˆngers are essential for the nuclear localization of MTF-1. Furthermore, allˆngers except the last are important for transcriptional activation function of MTF-1, suggesting their key role for MTF-1 function. Also, a cysteine cluster structure located in the C-terminal region of MTF-1 is critical for transactivating function of MTF-1. These results suggest a central role of the Znnger domain and intramolecular cooperation through a structural change of MTF-1 for its response to heavy metal challenge.

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Perspectives on Cadmium Toxicity Research.

Satoh

Koyama

Kaji

et al. 2002

Tohoku J. Exp. Med.

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Since there are a plethora of studies on cadmium toxicity and poisoning in laboratory animals and humans, we have limited this review to studies that are relevant to human health issues by focusing on carcinogenicity, genotoxicity, circulatory disease, nephrotoxicity and life expectancy. Cadmium exposure has been established to induce cancer in various tissues of laboratory animals. Contrary to early findings of the lack of genotoxicity by cadmium, recent findings of mammalian cell culture studies have revealed genotoxic effects. Furthermore, cadmium exposure at relatively low doses induces circulatory diseases in laboratory animals. Despite such results of various cadmium toxicities in animal studies, data from human studies are lacking and insufficient to support the cause-effect relationship. Although cadmium is currently considered to be a human carcinogen by the International Agency for Research and Cancer, it is inappropriate to conclude that sufficient evidence on the carcinogenicity of cadmium in humans exists. It is also thought that epidemiological studies so far reported do not support the occurrence of cadmium-induced circulatory disease in humans. Since there are inconsistent reports on the relationship of cadmium exposure with the life expectancy of people living in cadmium-polluted areas, further studies are needed for clarification. It is also necessary to examine apparent discrepancies in result between humans and experimental animals. It has been established that long-term exposure to cadmium causes renal dysfunction in both humans and experimental animals, and whether there are any differences in the inducibility of metallothionein in the kidney warrants further study.

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Original MRE-binding Transcriptional Factor Gene in Normal Humans is ZRF, not MTF-1.

Cited by 3 publications

References 25 publications

Potential effect on cellular response to cadmium of a single-nucleotide A → G polymorphism in the promoter of the human gene for metallothionein IIA

Potential effect on cellular response to cadmium of a single-nucleotide A → G polymorphism in the promoter of the human gene for metallothionein IIA

Mechanism of Metallothionein Gene Activation Mediated by Heavy-metal Dependent Transcription Factor MTF-1

Perspectives on Cadmium Toxicity Research.

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