Disease relevance of Mt3

• Similar reductions in zinc accumulation and neuronal death in hippocampal CA1 and the dentate gyrus in Mt3-null mice were observed in a sodium nitroprusside model of acute brain injury [1].
• Acupuncture could improve zinc ion bioavailability, by maintaining the balance between MT1 and MT3 mRNA expression levels and might explain one of the mechanisms by which acupuncture treatments defer aging and treat some age-related neurodegenerative diseases [2].
• Deletion of the CTG repeat or of the JC virus silencer did not promote MT-3 promoter activity in nonpermissive cells, or enhance expression in permissive cells [3].
• Characterization of cis-acting elements in the promoter of the mouse metallothionein-3 gene. Activation of gene expression during neuronal differentiation of P19 embryonal carcinoma cells [3].
• Culture supernatants from ATL cells (ATL-SN) obtained from the peripheral blood constitutively produced an interleukin-1 (IL-1)-like factor in vitro, as shown by the growth inhibition factor (GIF) assay using the A375 melanoma cell line and the lymphocyte activating factor (LAF) assay using C3H/HeJ thymocytes [4].

Psychiatry related information on Mt3

• Indeed, studies report that MT-3 is decreased by ~30% in brains of patients with Alzheimer disease (AD) [5].
• It is concluded that, at non-cytotoxic concentrations, MT-II and MT-III activate defense mechanisms in macrophages up regulating phagocytosis, mainly via mannose and beta-glucan receptors, and the respiratory burst [6].

High impact information on Mt3

• The antigen-specific GEF enhanced the antibody response, and antigen-specific GIF suppressed the antibody response, both in carrier specific manner [7].
• Mouse MT-III gene expression appears to be restricted to brain; in addition, it fails to respond to zinc, cadmium, dexamethasone, or bacterial endotoxin in vivo, thereby distinguishing MT-III from other known MTs [8].
• The MT-III genes are closely linked to the other functional MT genes on human chromosome 16 and mouse chromosome 8 [8].
• Electrophoretic mobility shift assays demonstrate that Egr-1 is involved in the TKE complex that binds to the MT3 element and that expression of Egr-1 induces transcription of a mouse TK-chloramphenicol acetyltransferase reporter in transient transfections [9].
• This is followed by activation of genes involved in metal ion regulation (metallothionein-I, metallothionein-III, ferritin-H, and ferritin-L) at 4 months of age just prior to end-stage disease, perhaps as an adaptive response to the mitochondrial destruction caused by the mutant protein [10].

Biological context of Mt3

• The main results are: (1) MT-III and IL-6 gene expressions increase in the hippocampus from old mice, in comparison with young and very old mice [11].
• In conclusion, low MT-III in the hippocampus from young and very old mice leads to good zinc ion bioavailability that it is upstream coupled with normal hippocampal function affecting downstream normal thyroid hormones turnover and satisfactory NK cell activity, via complete saturation of zinc-bound active thymulin molecules [11].
• Metallothionein-III (MT-III) a brain-specific member of metallothionein family contributes to zinc neuronal homeostasis, and zinc is an important regulator of many brain functions, including the activity of hormone realising factors by hippocampus [11].
• MT-III protein content was determined by a cadmium-binding assay, and the MT mRNA level was measured by reverse transcription followed by polymerase chain reaction (RT-PCR) [12].
• Mice lacking MT-III because of targeted gene inactivation were generated to evaluate the neurobiological significance of MT-III [13].

Anatomical context of Mt3

• After kainate-induced seizures, cytoplasmic zinc accumulation and neuronal death in the hippocampal CA1 region and the thalamus were substantially lower in Mt3-null mice than in wild-type mice [1].
• Role of metallothionein-III following central nervous system damage [14].
• Thus, MT-III could not only affect neuronal sprouting as previously suggested, but also astrocyte function [15].
• In contrast, MT-III and MT-IV mRNAs were both abundant in the maternal deciduum, and in experimentally induced deciduoma on 7 and 8 days postcoitum (1 dpc = vaginal plug), as are MT-I and -II mRNAs [16].
• Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles [17].

Associations of Mt3 with chemical compounds

• In contrast to CA1, more neuronal death occurred after kainate-induced seizures in CA3 of Mt3-null mice [1].
• 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 [18].
• Therefore, Cd, Zn, and Dex induced MT-I and -II mRNA but not MT-III mRNA in astrocytes [19].
• MT-III-deficient mice were more susceptible to seizures induced by kainic acid and subsequently exhibited greater neuron injury in the CA3 field of hippocampus [13].
• Interestingly, the MT-I inducers, Cd, Dex, ethanol, and KA, down-regulated brain MT-III mRNA levels by approx. 30% [20].

Physical interactions of Mt3

• 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 [21].
• Organs from mice deleted for NRH:quinone oxidoreductase 2 are deprived of the melatonin binding site MT3 [22].

Regulatory relationships of Mt3

• 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) [20].
• MT-III induced a larger neutrophil infiltrate than MT-II [23].

Other interactions of Mt3

• Solution NMR was utilized to determine the structural and dynamic differences of MT-3 from MT-1 and 2 [18].
• Furthermore, compared with zinc transporter 3 (Znt3)-null mice, Znt3/Mt3 double-null mice exhibited further reductions in neuronal death in CA1 following kainate-induced seizures [1].
• MT-I and MT-II are expressed in many tissues, including the brain, whereas MT-III is expressed mainly in the central nervous system [24].
• In contrast, Mt3-null mice showed increased expression of several neurotrophins as well as of the neuronal sprouting factor GAP-43 [14].
• Coimmunoprecipitation experiments, also conducted on whole mouse brain extract using the anti-mouse MT-3 antibody along with commercially available antibodies against HSP84 and CK, confirmed that these three proteins were in a single protein complex [5].

Analytical, diagnostic and therapeutic context of Mt3

• METHODS: Semiquantitative RT-PCR was used to determine brain mRNA levels of MT-I and MT-III in 4 inbred mouse strains with variable EP [25].
• Both MT-III protein content and mRNA expression in the brains of MT-null mice were not affected by exposure to whole-body irradiation [12].
• The distribution of MT-III mRNA within the adult brain was determined by solution and in situ hybridization and compared to that of MT-I mRNA [17].
• MT-III expression was significantly increased in the Purkinje cell layer and basal nuclei of the cerebellum, which was confirmed by Northern blot analysis of poly(A)+ mRNA and by ELISA of the MT-III protein [26].
• Acupuncture altered the expression levels of MT1 and MT3 mRNA and differences between the effects of the two stimulated acupoints were seen [2].

References