The four members of the <i>Drosophila</i> metallothionein family exhibit distinct yet overlapping roles in heavy metal homeostasis and detoxification

Egli, Dieter; Doménech, J.; Selvaraj, Anand; Balamurugan, Krishnaswamy; Hua, Haiqing; Capdevila, Mercè; Georgiev, Oleg; Schaffner, Walter; Atrian, Sı́lvia

doi:10.1111/j.1365-2443.2006.00971.x

Cited by 102 publications

(92 citation statements)

References 26 publications

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“…This selective induction mirrors the protective effects of the genes. MtnA is more protective against Cu exposure, and MtnB is more protective against Cd (14). Similar selective protective effects are evident from human toxicity data where mutations in the MTIIA gene increase susceptibility to Cd toxicity, but not Zn or Cu (20,21).…”

supporting

confidence: 62%

“…However, MtnA expression is stimulated more effectively by Cu than by Cd. By contrast, MtnB expression is stimulated more by Cd than by Cu (14,16). The same type of metal-specific activation occurs in mammalian cells and likely reflects a fundamental aspect of the metal discrimination system (17)(18)(19).…”

mentioning

confidence: 91%

“…An interesting aspect of MT regulation is that the level of expression varies depending on the specific metal insult (14,15). As an example, in Drosophila cells, exposure to heavy metals results in increased expression of the MT genes MtnA and MtnB.…”

mentioning

confidence: 99%

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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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confidence: 62%

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confidence: 91%

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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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“…Metal specificity of MT isoforms has been proven in invertebrate taxa, such as the gastropod Helix pomatia (Dallinger et al, 1997) and D. melanogaster (Egli et al, 2006a) based on induction and binding efficiency measurements. In these species a Cu-and a Cd-specific MT were identified.…”

Section: The Mt Systemmentioning

confidence: 99%

Molecular mechanisms of heavy metal tolerance and evolution in invertebrates

Janssens¹,

Roelofs²,

Straalen³

2009

Insect Science

144

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Following the genomics revolution, our knowledge of the molecular mechanisms underlying defenses against stress has been greatly expanded. Under strong selective pressure many animals may evolve an enhanced stress tolerance. This can be achieved by altering the structure of proteins (through mutations in the coding regions of genes) or by altering the amount of protein (through changes in transcriptional regulation). The latter type of evolution can be achieved by substitutions in the promoter of the gene of interest (cisregulatory change) or by altering the structure or amount of transcriptional regulator proteins (trans-regulatory change). The metallothionein system is one of the best studied stress response systems in the context of heavy metals. Metallothionein expression is assumed to be regulated by metal transcription factor 1 (MTF-1); however, up to now the involvement of MTF-1 has only been proven for some vertebrates and Drosophila. Data on invertebrates such as nematodes and earthworms suggest that other mechanisms of metallothionein induction may be present. A detailed study of Cd tolerance was done for a species of soilliving springtail, Orchesella cincta. The metallothionein gene of this species is overexpressed in metal-exposed field populations. Analysis of the metallothionein promoter has demonstrated extensive polymorphisms that have a functional significance, as shown in bioreporter assays. In a study comparing 20 different populations, the frequency of a high-expresser promoter allele was positively correlated with the concentration of metals in soil, especially Cd. The springtail study shows that cis-regulatory change of genes involved in the cellular stress response may contribute to evolution of metal tolerance.

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“…MtnA is the most important under copper load, while MtnB preferentially binds cadmium and protects against cadmium intoxication. MtnC and MtnD, despite sharing 67% amino acid identity with MtnB, have only a minor role in protection against heavy metals, at least when MtnA and MtnB are present (16,18). The MtnA and MtnB genes (also referred to as Mtn and Mto, respectively) are differentially regulated during development (61).…”

mentioning

confidence: 99%

The parkin Mutant Phenotype in the Fly Is Largely Rescued by Metal-Responsive Transcription Factor (MTF-1)

Saini

Georgiev

Schaffner

2011

Molecular and Cellular Biology

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The gene for Parkin, an E3 ubiquitin ligase, is mutated in some familial forms of Parkinson's disease, a severe neurodegenerative disorder. A homozygous mutant of the Drosophila ortholog of human parkin is viable but results in severe motoric impairment including an inability to fly, female and male sterility, and a decreased life span. We show here that a double mutant of the genes for Parkin and the metal-responsive transcription factor 1 (MTF-1) is not viable. MTF-1, which is conserved from insects to mammals, is a key regulator of heavy metal homeostasis and detoxification and plays additional roles in other stress conditions, notably oxidative stress. In contrast to the synthetic lethality of the double mutant, elevated expression of MTF-1 dramatically ameliorates the parkin mutant phenotype, as evidenced by a prolonged life span, motoric improvement including short flight episodes, and female fertility. At the cellular level, muscle and mitochondrial structures are substantially improved. A beneficial effect is also seen with a transgene encoding human MTF-1. We propose that Parkin and MTF-1 provide complementary functions in metal homeostasis, oxidative stress and other cellular stress responses. Our findings also raise the possibility that MTF-1 gene polymorphisms in humans could affect the severity of Parkinson's disease.Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disorder and the most common age-related movement disorder (10,13,43,59). Many molecular aspects of PD pathogenesis still need to be clarified. Extensive studies point to oxidative stress as a major contributor to the disease (28). Besides the gene for Parkin, an E3 ubiquitin ligase, four other genes, PINK1, DJ1, UCHL1, and ␣-synuclein, have been implicated in rare, early-onset, familial forms of PD, whereas LRRK2 is predominantly responsible for late-onset PD (20,57,70). Much effort has gone into the development of animal models of PD, including models in the fly Drosophila melanogaster. In the studies presented here, we use a strain in which the ortholog of the human parkin gene has been disrupted by the insertion of a P-element transposon into the coding region (24,48).In mammals, the proteins PINK1 and Parkin cooperate to ensure proper quality control of mitochondria, and Parkin is particularly important for autophagy of faulty mitochondria (reviewed in references 8 and 73). In agreement with this notion, Parkin deficient flies suffer from mitochondrial malfunction (24, 45, 48), which distorts muscle structure and causes severe locomotor defects and an inability to fly (24, 48). Furthermore, both male and female parkin-null Drosophila mutants are sterile (52), exhibit an increased sensitivity to multiple stresses (including oxidative stress), and have a reduced life span (23, 48).Maintenance of metal homeostasis is an essential requirement for the proper functioning of all organisms. An adequate supply of essential trace metals, such as copper and zinc, is important, whereas an excess can be highly t...

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The four members of the Drosophila metallothionein family exhibit distinct yet overlapping roles in heavy metal homeostasis and detoxification

Cited by 102 publications

References 26 publications

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

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

Molecular mechanisms of heavy metal tolerance and evolution in invertebrates

The parkin Mutant Phenotype in the Fly Is Largely Rescued by Metal-Responsive Transcription Factor (MTF-1)

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