Cadmium-mediated Activation of the Metal Response Element in Human Neuroblastoma Cells Lacking Functional Metal Response Element-binding Transcription Factor-1

Chu, Waihei A.; Moehlenkamp, Jeffrey D.; Bittel, Douglas C.; Andrews, Glen K.; Johnson, Jeffrey A.

doi:10.1074/jbc.274.9.5279

Cited by 27 publications

(16 citation statements)

References 38 publications

(46 reference statements)

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“…In addition, cadmium induces oxidative stress and produces several kinds of cytokines, both of which are known to induce the synthesis of MT. This suggests that mechanisms other than MTF-1 activation may also be involved in the induction of MT by cadmium (Chu et al, 1999). Thus, the molecular mechanisms of MT induction by nonzinc metal compounds still remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Induction of Metallothionein by Manganese Is Completely Dependent on Interleukin-6 Production

Kobayashi¹,

Kuroda²,

Shibata³

et al. 2006

J Pharmacol Exp Ther

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Metallothionein (MT) is a cysteine-rich protein that binds to and is inducible by heavy metals such as cadmium and zinc. However, the precise mechanism of MT induction by other metals remains unclear. In the present study, we investigated the mechanism of MT induction by manganese, focusing on the involvement of cytokine production. Administration of MnCl 2 to mice resulted in the induction of MT dose-dependently in the liver with little accumulation of manganese. Speciation analysis of metals in the liver cytosol showed that the major metal bound to the induced MT was zinc. Administration of MnCl 2 caused an increase in mRNA levels of interleukin-6 (IL-6) in the liver as well as an increase in serum levels of IL-6 but not those of other inflammatory cytokines. Subsequently, serum levels of serum amyloid A (SAA), an acute-phase protein induced by IL-6, increased with a peak at 24 h. However, no increase in serum alanine aminotransferase activity was observed, suggesting that manganese enhanced the production of IL-6 and SAA without causing liver injury. In response to IL-6, the expression of a zinc transporter, ZIP14, was enhanced in the liver, possibly contributing to the synthesis of hepatic zinc-MT. In IL-6-null mice, the induction of hepatic MT by treatment with MnCl 2 was completely suppressed to the control level. These results suggest that manganese is a unique metal that induces the synthesis of hepatic MT completely depending on the production of IL-6 without accompanying liver injury.Metallothionein (MT) is a cysteine-rich low-molecularweight protein with a high affinity for heavy metals. Physiological roles of MT encompass a broad spectrum, including detoxification of heavy metals, scavenging of free radicals, regulation of cell growth, and maintenance of homeostasis of trace metals such as zinc and copper (Suzuki et al., 1993). The most prominent characteristic of MT is its inducibility not only by metals but also by various factors such as hormones, cytokines, organic chemicals, starvation, and physical stress (Kä gi, 1993). It is generally perceived that the expression of the MT gene in response to a metal load is regulated by metal-responsive transcription factor 1 (MTF-1) that binds to the metal-response elements of the promoter region of MT genes (Heuchel et al., 1994). The mechanisms underlying the activation of the MT gene through the interaction of MTF-1 and metal-response elements have been investigated extensively (Andrews, 2001;Otsuka, 2004), but the precise mechanism of MT induction by nonzinc metals, including cadmium has been poorly understood (Daniels et al., 2002;Wang et al., 2004).In addition to potent MT-inducing metals such as zinc, cadmium, copper, mercury, silver, and bismuth, other metals such as chromium, iron, cobalt, nickel, arsenic, and manganese can also induce MT but to the lesser levels (Fleet et al., 1990;Albores et al., 1992). These weak MT-inducing metals

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Section: Discussionmentioning

confidence: 99%

Induction of Metallothionein by Manganese Is Completely Dependent on Interleukin-6 Production

Kobayashi¹,

Kuroda²,

Shibata³

et al. 2006

J Pharmacol Exp Ther

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“…Little is known about those interactions or the interactions of MTF-1 with other proteins; thus, the second and third possibilities remain to be addressed. With regard to the fourth possibility, we recently found that MRE activity can be increased in the absence of detectable MTF-1 in IMR cells (35). Cadmium-responsive factor(s) that can interact with MREs in vitro have been reported previously (8, 36 -38), but the functional significance, if any, of those factors has not been determined.…”

Section: An Overtly Toxic Concentration Of Cadmium Can Induce Nuclearmentioning

confidence: 95%

Zinc and Cadmium Can Promote Rapid Nuclear Translocation of Metal Response Element-binding Transcription Factor-1

Smirnova

Bittel

Ravindra

et al. 2000

Journal of Biological Chemistry

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204

148

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Metal response element-binding transcription factor-1 (MTF-1) is a six-zinc finger protein that plays an essential role in activating metallothionein expression in response to the heavy metals zinc and cadmium. Low affinity interactions between zinc and specific zinc fingers in MTF-1 reversibly regulate its binding to the metal response elements in the mouse metallothionein-I promoter. This study examined the subcellular distribution and DNA binding activity of MTF-1 in cells treated with zinc or cadmium. Immunoblot analysis of cytosolic and nuclear extracts demonstrated that in untreated cells, about 83% of MTF-1 is found in the cytosolic extracts and is not activated to bind to DNA. In sharp contrast, within 30 min of zinc treatment (100 microM), MTF-1 is detected only in nuclear extracts and is activated to bind to DNA. The activation to bind to DNA and nuclear translocation of MTF-1 occurs in the absence of increased MTF-1 content in the cell. Furthermore, immunocytochemical localization and immunoblotting assays demonstrated that zinc induces the nuclear translocation of MTF-1-FLAG, expressed from the cytomegalovirus promoter in transiently transfected dko7 (MTF-1 double knockout) cells. Immunoblot analysis of cytosolic and nuclear extracts from cadmium-treated cells demonstrated that concentrations of cadmium (10 microM) that actively induce metallothionein gene expression cause only a small increase in the amount of nuclear MTF-1. In contrast, an overtly toxic concentration of cadmium (50 microM) rapidly induced the complete nuclear translocation and activation of DNA binding activity of MTF-1. These studies are consistent with the hypothesis that MTF-1 serves as a zinc sensor that responds to changes in cytosolic free zinc concentrations. In addition, these data suggest that cadmium activation of metallothionein gene expression may be accompanied by only small changes in nuclear MTF-1.

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“…Briefly, dko7 (MTF-1 Ϫ/Ϫ ) cells were transfected and assayed for reporter gene expression as described (22,29). SL2 cells were transfected using the calcium phosphate transfection system kit (Life Technologies, Inc.) according to the manufacturer's suggestions.…”

Section: Methodsmentioning

confidence: 99%

Functional Heterogeneity in the Zinc Fingers of Metalloregulatory Protein Metal Response Element-binding Transcription Factor-1

Bittel

Smirnova

Andrews

2000

Journal of Biological Chemistry

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Metal response element-binding transcription factor-1 (MTF-1) is a unique, zinc-inducible transcription factor that binds to metal response elements in the metallothionein promoter and activates transcription in response to metals and oxidative stress. MTF-1 contains six zinc fingers of the Cys 2 -His 2 type. It was previously shown that MTF-1 is reversibly activated to bind DNA in response to changes in zinc status, unlike other zinc finger transcription factors, which do not appear to be reversibly activated by zinc in the cellular environment. Here we show that zinc fingers 2-4 constitute the core DNA-binding domain, whereas fingers 5 and 6 appear to be unnecessary for DNA binding in vitro. Deletion of finger 1 resulted in a protein that bound DNA constitutively in vitro. Furthermore, transfer of MTF-1 finger 1 to a position immediately preceding the three zinc fingers of Sp1 resulted in a chimeric protein that required exogenous zinc to activate DNA binding in vitro, unlike native Sp1, which binds DNA constitutively. Transient transfection experiments demonstrated that intact MTF-1 activated a reporter 2.5-4-fold above basal levels after metal treatment in mouse MTF-1 knockout cells, Drosophila SL2 cells, and yeast. However, the metal response was lost in all three systems when finger 1 was deleted, but was unaffected by deletion of fingers 5 and 6. These data suggest that finger 1 of MTF-1 constitutes a unique metal-sensing domain that, in cooperation with the transactivation domains, produces a zinc-sensing metalloregulatory transcription factor. Metallothioneins (MTs)1 constitute a conserved family of cysteine-rich heavy metal-binding proteins (1). In the mouse, MT-I and MT-II display a wide tissue distribution and have been demonstrated to participate in zinc homeostasis (2), detoxification of cadmium (3, 4), and protection against oxidative stress (5). MT gene transcription is induced dramatically by heavy metals (especially zinc and cadmium) (6). Metal response elements (MREs) are essential for metal induction, and there are multiple copies of the MREs in the proximal promoters of MT genes. MREs were initially shown to mediate the transcriptional response of MT genes to metals (7) and, more recently, to participate in the transcriptional response to oxidative stress (8, 9).MRE-binding transcription factor-1 (MTF-1) was cloned (10, 11) and found to be a six-zinc finger transcription factor in the Cys 2 -His 2 family. Targeted disruption of both MTF-1 alleles in mouse embryonic stem cells demonstrated its essential role for basal as well as heavy metal-induced MT gene expression (12). Unlike other zinc finger transcription factors, which appear to be constitutively active to bind DNA under normal physiological conditions, MTF-1 is reversibly activated to bind DNA in response to changes in zinc availability (9,10,(13)(14)(15)(16). This reversible activation involves direct interaction between zinc and the zinc finger domain of MTF-1. Activation of MTF-1 in response to zinc is reminiscent of copper activat...

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Cadmium-mediated Activation of the Metal Response Element in Human Neuroblastoma Cells Lacking Functional Metal Response Element-binding Transcription Factor-1

Cited by 27 publications

References 38 publications

Induction of Metallothionein by Manganese Is Completely Dependent on Interleukin-6 Production

Induction of Metallothionein by Manganese Is Completely Dependent on Interleukin-6 Production

Zinc and Cadmium Can Promote Rapid Nuclear Translocation of Metal Response Element-binding Transcription Factor-1

Functional Heterogeneity in the Zinc Fingers of Metalloregulatory Protein Metal Response Element-binding Transcription Factor-1

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