Metal Response Element (MRE)-Binding Transcription Factor-1 (MTF-1): Structure, Function, and Regulation

Giedroc, D.P.; Chen, Xiaohua; Apuy, Julius L.

doi:10.1089/15230860152542943

Cited by 153 publications

(118 citation statements)

References 73 publications

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“…We have recently identified and characterized dMTF-1, the MTF-1 homolog of the fruit fly Drosophila (Zhang et al, 2001;Egli et al, 2003). In both mammals and Drosophila, MTF-1 requires zinc and its function is compromised by direct exposure to other heavy metals (Bittel et al, 1998;Giedroc et al, 2001;Zhang et al, 2001). Accordingly, in a cell-free transcription system, MTF-1 activation by cadmium and copper (and H 2 O 2 ) was shown to occur indirectly, via release of zinc from metallothionein (for convenience, the designations Zn or zinc, Cu or copper, Cd or cadmium and Hg or mercury are also used here to denote Zn 2q , Cu 2q , Cd 2q and Hg 2q , respectively.)…”

Section: Introductionmentioning

confidence: 99%

Metal-responsive transcription factor (MTF-1) and heavy metal stress response in Drosophila and mammalian cells: a functional comparison

Balamurugan

Egli²,

Selvaraj³

et al. 2004

Biological Chemistry

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The zinc finger transcription factor MTF-1 (metal-responsive transcription factor-1) is conserved from insects to vertebrates. Its major role in both organisms is to control the transcription of genes involved in the homeostasis and detoxification of heavy metal ions such as Cu 2q , Zn 2q and Cd 2q . In mammals, MTF-1 serves at least two additional roles. First, targeted disruption of the MTF-1 gene results in death at embryonic day 14 due to liver degeneration, revealing a stage-specific developmental role. Second, under hypoxic-anoxic stress, MTF-1 helps to activate the transcription of the gene placental growth factor (PlGF), an angiogenic protein. Recently we characterized dMTF-1, the Drosophila homolog of mammalian MTF-1. Here we present a series of studies to compare the metal response in mammals and insects, which reveal common features but also differences. A human MTF-1 transgene can restore to a large extent metal tolerance to flies lacking their own MTF-1 gene, both at low and high copper concentrations. Likewise, Drosophila MTF-1 can substitute for human MTF-1 in mammalian cell culture, although both the basal and the metal-induced transcript levels are lower. Finally, a clear difference was revealed in the response to mercury, a highly toxic heavy metal: metallothionein-type promoters respond poorly, if at all, to Hg 2q in mammalian cells but strongly in Drosophila, and this response is completely dependent on dMTF-1.

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Section: Introductionmentioning

confidence: 99%

Metal-responsive transcription factor (MTF-1) and heavy metal stress response in Drosophila and mammalian cells: a functional comparison

Balamurugan

Egli²,

Selvaraj³

et al. 2004

Biological Chemistry

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“…MTF-1 contains a single DNA binding domain consisting of six zinc fingers and it is structurally and functionally conserved from Drosophila to humans (6,7). Cross-species comparison between human and Drosophila MTF-1 reveals considerable identity in the DNA binding domain (66% amino acid identity) indicating that the proteins likely interact with DNA in a conserved mode (8,9).…”

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confidence: 99%

Single nucleotide in the MTF-1 binding site can determine metal-specific transcription activation

Sims

Chirn

Marr

2012

Proc. Natl. Acad. Sci. U.S.A.

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Cells respond to changes in environment by shifting their gene expression profile to deal with the new conditions. The cellular response to changes in metal homeostasis is an important example of this. Transition metals such as iron, zinc, and copper are essential micronutrients but other metals such as cadmium are simply toxic. The cell must maintain metal concentrations in a window that supports efficient metabolic function but must also protect against the damaging effects of high concentrations of these metals. One way a cell regulates metal homeostasis is to control genes involved in metal mobilization and storage. Much of this regulation occurs at the level of transcription and the protein most responsible for this is the conserved metal responsive transcription factor 1 (MTF-1). Interestingly, the nature of the changes in the gene expression profile depends on the type of exposure. The cell somehow senses the kind of the metal challenge and responds appropriately. We have been using the Drosophila system to try to understand the mechanism of this metal discrimination. Using genome-wide mapping of MTF-1 binding under different metal stresses we find that, surprisingly, MTF-1 chooses different DNA binding sites depending on the specific nature of the metal insult. We also find that the type of binding site chosen is an important component of the capability to induce the metal-specific transcription activation.heavy metal | MED26 D NA recognition by sequence-specific DNA binding transcription factors is the basic mechanism that links the cisregulatory information encoded in the genome with transcriptional control of gene expression. Although it is the DNA binding domain of these factors that dictates the sequence element bound by the protein, it is now clear that, at least for some factors, the DNA sequence of the binding site itself can influence the activation potential of the transcription factor (1, 2). Clearly the process of reading the genome and activating transcription is more intricate than a simple DNA binding event.Some transcription factors respond to signaling events and activate the transcription of different sets of genes in a signalspecific manner. The cellular response to changes in metal homeostasis is one example of this observation. The major transcription factor involved in metal homeostasis is the metal responsive element (MRE) binding transcription factor-1 (MTF-1) (for a recent review, see ref.3). MTF-1 is required for both constitutive and metal inducible transcription of some genes; it is also required for activated transcription of at least one gene in low metal conditions (4, 5). Thus, it responds to both excess and limiting metal conditions by activating different sets of genes.

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“…Zn 2+ , in turn, can directly bind to MTF-1 and promote its nuclear translocation (Chen et al, 2004;Smirnova et al, 2000), although it has also been suggested that Zn 2+ can bind to, and inactivate a yet unidentified inhibitor of the translocation process itself (Palmiter, 1994). Nonetheless, MTF-1 translocation to the nucleus and transactivation of MRE can serve as selective molecular indicators of elevations of intracellular Zn 2+ (Giedroc et al, 2001;Smirnova et al, 2000). An important objective of this work was to demonstrate the feasibility of using a molecular reporter for the liberation of Zn 2+ from intracellular binding sites in primary neuronal cultures.…”

Section: Discussionmentioning

confidence: 99%

“…It has been reported that MTF-1 plays an important role in the regulation of gene expression associated with zinc home-ostasis, including metallothionein (Giedroc et al, 2001) and the zinc transporter Znt-1 (Langmade et al, 2000). In neurons, regulation of the expression of these proteins may have important consequences on neuronal survival.…”

Section: Discussionmentioning

confidence: 99%

“…Zinc, but not other heavy metals, increases the binding activity of MTF-1 to MRE, which is present in multiple copies in the promoter region of metal-lothionein genes (Bittel et al, 1998;Koizumi et al, 1992Koizumi et al, , 1999Zhang et al, 2003). As such, MTF-1 serves as a selective intracellular Zn 2+ sensor to activate MT gene expression (Giedroc et al, 2001;Smirnova et al, 2000;Zhang et al, 2003). It has been demonstrated that in the absence of zinc, approximately 80% of cellular MTF-1 is found in the cytosol, and is unable to bind DNA (Smirnova et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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A molecular technique for detecting the liberation of intracellular zinc in cultured neurons

Hara

Aizenman²

2004

Journal of Neuroscience Methods

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We have previously reported that oxidative stimuli liberate Zn 2+ from metalloproteins, a phenomenon that can trigger neuronal cell death. Excessive intracellular Zn 2+ in many cell types triggers the expression of genes that encode metal binding proteins, such as metallothionein, via the activation and nuclear translocation of metal response element (MRE)-binding transcription factor-1 (MTF-1). Cd 2+ strongly induces nuclear translocation of MTF-1 in non-neuronal cells, but it does so by displacing Zn 2+ from its metal binding sites within the cell and increasing the intracellular concentration of this ion. Here, we describe the use of MRE-driven expression of a luciferase reporter gene as a sensitive molecular assay for detecting increases in intracellular zinc concentrations. MRE transactivation was induced in primary cortical neurons upon brief exposure to Zn 2+ or Cd 2+ . Enhanced MRE transactivation was observed upon co-exposure of neurons to Cd 2+ together with NMDA, as this metal can permeate through the receptor channel. Luciferase expression was observed regardless of whether or not neurons had been co-transfected with an MTF-1-containing plasmid, suggesting the presence of an endogenous MTF-1-like protein. Indeed, RT-PCR revealed that MTF-1 mRNA is present in neurons. In contrast, MTF-1 deficient dko7 cells were only observed to have MRE transactivation when co-transfected with MTF-1. Our results indicate that Cd 2+ can effectively induce transactivation of MRE in neurons by liberating Zn 2+ from its intracellular binding sites.

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Metal Response Element (MRE)-Binding Transcription Factor-1 (MTF-1): Structure, Function, and Regulation

Cited by 153 publications

References 73 publications

Metal-responsive transcription factor (MTF-1) and heavy metal stress response in Drosophila and mammalian cells: a functional comparison

Metal-responsive transcription factor (MTF-1) and heavy metal stress response in Drosophila and mammalian cells: a functional comparison

Single nucleotide in the MTF-1 binding site can determine metal-specific transcription activation

A molecular technique for detecting the liberation of intracellular zinc in cultured neurons

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