Disease relevance of Mt1

• Collectively, these results indicate that MDMA-induced toxicity to DA neurons is associated with increased Mt1 and Mt2 gene transcription and translation, possibly as part of a neuroprotective mechanism [1].
• Menkes kinky hair syndrome is an X-linked neurodegenerative disorder, causing tissue-specific increases in copper and metallothionein content [2].
• At age 14 weeks, the body weight and food intake of MT-null mice was 16 and 30% higher, respectively, compared with C57BL/6J mice [3].
• Metallothionein (MT) has several putative roles in metal detoxification, in Zn and Cu homeostasis, in scavenging free radicals, and in the acute phase response [3].
• Obesity and hyperleptinemia in metallothionein (-I and -II) null mice [3].

Psychiatry related information on Mt1

• Food deprivation (20 h) alone caused respective 14% and 30% decreases in hepatic and plasma Zn concentrations and a 27% reduction in total liver Zn reserves, whereas fasted normal mice conserved Zn with a 4-fold increase in hepatic MT [4].
• Metallothionein (MT)-III, originally discovered as a growth inhibitory factor (GIF), is a brain specific isomer of MTs and is markedly reduced in the brain of Alzheimer's disease patients (AD) and in several other neurodegenerative diseases [5].
• Defense mechanisms against cadmium toxicity. III. Effects of pretreatment with a small oral dose of cadmium on metallothionein synthesis after a large oral dose of cadmium in mice [6].
• Immediately after the exposure had ceased, total locomotor activity in OPF was decreased in the both strain of mice, although the MT-null mice appeared to show more distinct effect [7].
• Metallothionein (6 microg/g) significantly prolonged the latency period for inducing platelet plug formation in mesenteric venules [8].

High impact information on Mt1

• A murine model of Menkes disease reveals a physiological function of metallothionein [9].
• The lethality in Mo-brJ females can be explained by preferential inactivation of the paternal X chromosome in extraembryonic tissues and resultant copper toxicity in the absence of MT [9].
• Metallothionein-directed expression of TGF alpha in transgenic mice induced a spectrum of changes in the growth and differentiation of certain adult tissues [10].
• Neuron-specific alternative RNA processing in transgenic mice expressing a metallothionein-calcitonin fusion gene [11].
• Tissue-specific posttranslational processing of pre-prosomatostatin encoded by a metallothionein-somatostatin fusion gene in transgenic mice [12].

Chemical compound and disease context of Mt1

• Surprisingly, the appearance of metal responsiveness of the MT genes during development correlated with decreased Zn toxicity and increased Cd toxicity; two-cell embryos were Zn-sensitive and Cd-resistant, whereas eight-cell and older embryos were Zn-resistant and Cd-sensitive [13].
• Histopathological examination in ethanol-treated MT-null mice showed vacuolar degeneration, necrosis of the epithelial cells, and hemorrhage throughout the tunica mucosa [14].
• Retrovirally expressed metal response element-binding transcription factor-1 normalizes metallothionein-1 gene expression and protects cells against zinc, but not cadmium, toxicity [15].
• These data are interpreted to suggest that peroxynitrite ions are involved in the etiopathogenesis of Parkinson's disease, and metallothionein-mediated coenzyme Q10 synthesis may provide neuroprotection [16].
• Northern blot analysis revealed that metallothionein (MT) mRNAs accumulate after inhibition of protein synthesis with cycloheximide (CHX) in primary cultures of chick embryo hepatocytes and fibroblasts, as well as in an established mouse hepatoma cell line [17].

Biological context of Mt1

• Northern blot analysis confirmed the microarray findings and revealed a dynamic upregulation of Mt1 and Mt2 mRNA in the ventral midbrain within 4-12 hr after MDMA treatment [1].
• Most 22- to 39-week-old male MT-null mice were obese, as shown by increased fat accretion, elevated obese (ob) gene expression, and high plasma leptin levels, similar to those recorded in Zucker fatty (fa/fa) rats [3].
• Mice of mixed 129/Ola and C57BL/6J background with targeted disruption of MT-I and MT-II genes are more sensitive to toxic metals and oxidative stress [3].
• Regulation of zinc homeostasis by inducible NO synthase-derived NO: nuclear metallothionein translocation and intranuclear Zn2+ release [18].
• Mouse MT-I and MT-II genes are regulated by metals but not by glucocorticoids after transfection into HeLa cells [19].

Anatomical context of Mt1

• We show that metallothionein-I messenger RNA (mRNA) (mouse) and metallothionein-II mRNA (human) are elevated in mutant fibroblasts [2].
• Expression of MT-I in visceral endoderm cells was dependent on maternal dietary zinc [20].
• This nuclear Zn2+ release depends on the presence of MT as shown by the lack of this effect in activated endothelial cells from MT-deficient mice and temporally correlates with nuclear MT translocation [18].
• In the CD-1 strain, LPS induction of MT gene expression occurred in each of 10 organs examined (liver, kidney, pancreas, intestine, lung, heart, brain, ovary, uterus, and spleen) [21].
• In the oviduct, MT-I mRNA was not abundant in total RNA, but was detected specifically in the epithelial cells of the isthmus region and was elevated in these cells on D3 and D4 of gestation [13].

Associations of Mt1 with chemical compounds

• However, comparable dose-response curves in mutant and control cells are generated when mouse metallothionein-I mRNA concentrations are measured in cells exposed to varying concentrations of cadmium or copper (metallothionein inducers) [2].
• It has been shown that NO exogenously applied via NO donors resulting in nitrosative stress leads to cytoplasmic Zn2+ release from the zinc storing protein metallothionein (MT) and probably other proteins that complex Zn2+ via cysteine thiols [18].
• Mouse MT-I and MT-II mRNAs are induced to approximately the same extent in vivo in response to cadmium, dexamethasone, or lipopolysaccharide [19].
• In wild-type mice, MT-like immunoreactivity was increased in the inner retina (GCL and IPL) 12 and 24 hours after NMDA injection [22].
• Because of exchange broadening of a large number of the NMR signals from this domain, homology modeling was utilized to calculate models for the beta-domain and suggested that while the backbone fold of the MT-3 beta-domain is identical to MT-1 and 2, the second proline responsible for the activity, Pro9, may show structural heterogeneity [23].

Physical interactions of Mt1

• From the results of HPLC/ICP-MS analyses, it was concluded that the mercury components of MT-III and high molecular weight metal-binding proteins in the cerebellum of MT-I, II null mice were much higher than those of wild-type mice [24].
• These results show that a metal regulatory element of the mouse MT-1 gene interacts specifically with a nuclear protein of Mr 108,000 and that this protein is distinct from the transcription factor Sp1 [25].
• Specific antibodies to MT-2 were purified from our antiserum by affinity purification using CH-Sepharose 4B coupled with rat liver MT-1 [26].
• Conversely, the entire MT4 and both of its domains showed better Cu(I) binding properties than MT1, affording Cu(10)-MT4, Cu(5)-alphaMT4 and Cu(7)-betaMT4, stoichiometries that make the domain dependence toward Cu(I) clear [27].
• Putative zinc-sensing zinc fingers of metal-response element-binding transcription factor-1 stabilize a metal-dependent chromatin complex on the endogenous metallothionein-I promoter [28].

Co-localisations of Mt1

• MT-III mRNA hybridization signals were localized in hippocampus and co-localized with MT-I message in the glial cells of the Purkinje cell layer of the cerebellum [29].

Regulatory relationships of Mt1

• The transcription factors MTF-1 and USF1 cooperate to regulate mouse metallothionein-I expression in response to the essential metal zinc in visceral endoderm cells during early development [20].
• Transgenic expression of interleukin 6 in the central nervous system regulates brain metallothionein-I and -III expression in mice [30].
• Regulation of MT-I and MT-III mRNA was studied in brain and liver of control C57BL/6J mice and mice given chemicals known to increase MT-I, namely, lipopolysaccharide (LPS), zinc chloride (Zn), cadmium chloride (Cd), dexamethasone (Dex), ethanol, and kainic acid (KA) [29].
• MT-I mRNA hybridization signal was also enhanced in the olfactory bulbs from LPS- and Cd-treated mice, while this signal was present but weak in control brains [29].
• Administration of LPS to metallothionein (MT)-knockout (MT-KO) mice and 129/Sv wild-type (WT) controls at 4 mg/kg induced hepatic TNF-alpha elevation at 1.5 hours, followed by liver injury at 3 hours [31].
• Taken together, these studies show that NF1 acts synergistically with MTF-1 to activate the mouse MT-1 promoter in response to metal ions and tert-butylhydroquinone and contributes to maximal activation of the gene [32].

Other interactions of Mt1

• Furthermore, when mutant and control cells are grown to achieve overlapping intracellular copper concentrations in the two cell types, metallothionein-I (mouse) and metallothionein-II (human) mRNA levels are proportional to the intracellular copper concentrations [2].
• Metallothionein-I overexpression decreases brain pathology in transgenic mice with astrocyte-targeted expression of interleukin-6 [33].
• Solution NMR was utilized to determine the structural and dynamic differences of MT-3 from MT-1 and 2 [23].
• Metallothionein knockout and transgenic mice exhibit altered intestinal processing of zinc with uniform zinc-dependent zinc transporter-1 expression [34].
• Studies reported herein examine the expression and regulation of the MT-III and MT-IV genes in specific cell types in the maternal reproductive tract, developing embryo, and fetus known to express the MT-I and -II genes [35].

Analytical, diagnostic and therapeutic context of Mt1

• Targeted disruption of MT-I and MT-II genes seems to induce moderate obesity, providing a new obese animal model [3].
• MT-I mRNA in ova, preimplantation embryos, and oviducts was detected using in situ hybridization [13].
• RNA from preimplantation mouse embryos at different stages of development (Days 1 through 4 of gestation; D1 = vaginal plug) was analyzed using the reverse transcriptase-polymerase chain reaction (RT-PCR) to specifically amplify MT-I and MT-II mRNA transcripts [13].
• In wild-type mice, MT-I and -II immunohistochemistry was performed (with antibody that recognizes both proteins) 12 and 24 hours after intravitreous NMDA injection [22].
• MT-I + II deficiency decreased both astrogliosis and microgliosis and potentiated neuronal injury and apoptosis as shown by terminal deoxynucleotidyl transferase-mediated in situ end labelling (TUNEL), detection of single stranded DNA (ssDNA) and by increased interleukin-1beta-converting enzyme (ICE) and caspase-3 levels [36].

References