Effect of Stress on Mouse and Rat Brain Metallothionein I and III mRNA Levels

Belloso, Eva; Hernández, Jesús Avilla; Giralt, Mercedes; Kille, Peter; Hidalgo, Juan

doi:10.1159/000127149

Cited by 34 publications

(9 citation statements)

References 28 publications

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“…Previous studies on the stress-induced changes in MT expression used animals that were completely immobilized by fixing them to a board or enclosing them in a wrapping of metallic net (18,19), whereas this investigation utilized a mouse model system that has been explored extensively for determining the neuroendocrinological changes under stress (20,22,23,34,48,49). The merit of this model system is that the animals are free to move around, and the only restriction is the inability to turn around in the conical tube.…”

Section: Discussionmentioning

confidence: 99%

Metallothionein Induction in Response to Restraint Stress

Ghoshal¹,

Wang²,

Sheridan³

et al. 1998

Journal of Biological Chemistry

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Metallothioneins (MT) have been implicated in the protection of cells from oxidative stress. We studied the molecular mechanism of induction of MT-I and MT-II in response to restraint stress using a mouse model system in which the animals were restrained in well ventilated polypropylene tubes for 12 h each day (one cycle). Here, we show that MT-I and MT-II mRNA levels were elevated as much as 10 -20-fold after just one cycle of this simple stress. Stress-mediated MT induction occurred at the transcriptional level. The level of MT mRNA correlated with the stress-induced increase, and not with the diurnal variation, in the level of serum glucocorticoid. Treatment of the mice with RU 486, a glucocorticoid receptor antagonist, prior to restraint stress inhibited MT induction by at least 50%. Furthermore, the glucocorticoid responsive element-binding activity in the liver nuclear extracts from the stressed mice was significantly higher than that in the control mice. The complex formations between the transcription factor Sp1, MTF1, or MLTF/ ARE and the respective specific oligonucleotides were not altered in the liver from the stressed mouse. The MT mRNA levels returned to the basal level at the end of nine cycles of stress, indicating habituation of the animals to restraint stress. At this stage, exposure of the animals to another type of stress, treatment with heavy metals, resulted in further induction of MT. These data indicate that glucocorticoid is the primary physiological factor responsible for MT induction following restraint stress, and the glucocorticoid receptor is the major transcription factor involved in this process. Metallothionein (MT)1 genes that encode low molecular mass, cysteine-rich, heavy metal-binding proteins have been reported in a wide variety of organisms (for reviews, see Refs. 1-4). The members of the MT superfamily are usually devoid of aromatic amino acids, and each mole of the protein can bind up to 7-12 g atoms of transition metal through the abundant cysteine residues. Of the four isoforms of MT, MT-I and MT-II have been studied the most. Although detoxification of heavy metals has been considered an important function of MT, recent studies have suggested a significant role for MT-I and MT-II in copper homeostasis (1, 3, 5), as a donor of zinc for the zinc-dependent transcription factors (4), and as a free radical scavenger in the protection of cells against reactive oxygen intermediates (6, 7) and electrophilic anticancer drugs (8). These MT isoforms are transcriptionally induced in response to different stimuli that include steroid hormones, interleukins, phorbol esters, and interferons (1, 3). Several lines of evidence suggest that metallothioneins can protect cells from damage caused by a variety of agents. For example, overexpression of MT in cells diminishes the sensitivity of the cells to the compounds that generate free oxygen radicals (6, 7), DNA-damaging agents such as UV radiation, nitric oxide (2, 9, 10), and certain anticancer drugs (8, 11), whereas targeted disruption...

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Section: Discussionmentioning

confidence: 99%

Metallothionein Induction in Response to Restraint Stress

Ghoshal¹,

Wang²,

Sheridan³

et al. 1998

Journal of Biological Chemistry

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“…The isoforms, MT3 and MT1, respond differently to zinc deprivation of cells in culture with only MT1 being down-regulated in these cells [7]. Transcriptional regulation of MT3 levels is differentially regulated compared to MT1 and MT2 [8][9][10][11]. These data suggest that MT3 is not involved in metal ion homeostasis, as the MT1 and MT2 isoforms seem to be.…”

Section: Introductionmentioning

confidence: 91%

Antiserum specific for the intact isoform-3 of metallothionein

Tokheim

Armitage

Martin

2005

Journal of Biochemical and Biophysical Methods

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“…Data generated in vivo and in primary neuronal and glial cell cultures demonstrate that mMT-I mRNA and protein are increased in response to metals (14 -20), immobilization stress (19), steroids (17,18,20,21), and lipopolysaccarides (21,22). These data imply that neurons and glia possess the components necessary for transcriptional activation of mMT-I.…”

Section: Metallothioneins (Mts)mentioning

confidence: 99%

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

Chu¹,

Moehlenkamp²,

Bittel³

et al. 1999

Journal of Biological Chemistry

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Metal response element-binding transcription factor-1 (MTF-1) binds specifically to metal response elements (MREs) and transactivates metallothionein (MT) gene expression in response to zinc and cadmium. This investigation contrasts the mechanism of mouse MT gene (mMT-I) promoter activation by cadmium and zinc in IMR-32 human neuroblastoma cells to determine whether MTF-1 binding to the MRE is necessary for activation by these metals. Cadmium activated a mMT-1 promoter (؊150 base pairs) luciferase reporter 20 -25-fold through a MRE-dependent mechanism. In contrast, zinc had little effect on the mMT-1 luciferase reporter. IMR-32 cells lacked MRE binding activity, and treatment with zinc in vitro or in vivo did not generate a MTF-1⅐MRE complex, suggesting that IMR-32 cells lack functional MTF-1. Overexpression of mMTF-1 regenerated a zinc-mediated induction of the MRE without affecting cadmium activation. Because no other transition metals tested activated the MRE, this effect appeared to be cadmium-specific. These data demonstrate that in IMR-32 human neuroblastoma cells, zinc and cadmium can use independent mechanisms for activation of the mMT-I promoter and cadmium-mediated MRE activation is independent of MTF-1 and zinc.

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Effect of Stress on Mouse and Rat Brain Metallothionein I and III mRNA Levels

Cited by 34 publications

References 28 publications

Metallothionein Induction in Response to Restraint Stress

Metallothionein Induction in Response to Restraint Stress

Antiserum specific for the intact isoform-3 of metallothionein

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

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