Affinage

MT3

Metallothionein-3 · UniProt P25713

Round 2 corrected
Length
68 aa
Mass
6.9 kDa
Annotated
2026-04-28
130 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MT3 (metallothionein-3/GIF) is a brain-enriched, cysteine-rich metalloprotein that coordinates Cu(I) and Zn(II) in distinct metal-thiolate clusters—a Cu4-thiolate cluster preferentially in the N-terminal beta-domain and an M4S11 cluster in the C-terminal alpha-domain—enabling it to function as a dynamic zinc buffer in neurons and to suppress redox-active Cu(II)-amyloid complexes via transmetallation (PMID:10830840, PMID:21320589). Its cysteine thiolates confer potent hydroxyl radical scavenging activity that exceeds MT-I/II, protecting neurons and non-neural cells from oxidative damage (PMID:12058024, PMID:12383939). MT3 regulates lysosomal integrity and autophagic flux through zinc dynamics; under oxidative stress, zinc released from MT3 triggers lysosomal membrane permeabilization and cell death, while MT3 absence reduces lysosomal capacity (PMID:20974010). MT3 is transcriptionally silenced by CpG island hypermethylation in gastric carcinoma and pediatric AML, and its re-expression induces apoptosis and inhibits proliferation in cancer cells (PMID:12538345, PMID:24962166).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1991 High

    Identification of MT3 as a neuron growth-inhibitory factor resolved the molecular identity of a brain-specific metalloprotein that directly suppresses cortical neuronal survival and neurite outgrowth.

    Evidence Purification from human brain with amino acid sequencing and in vitro cortical neuron assay

    PMID:1873033

    Open questions at the time
    • Mechanism of neurite inhibition unknown
    • Whether reduced MT3 in AD astrocytes is causative or consequential not resolved
  2. 1992 High

    Cloning established MT3 as a distinct metallothionein gene with brain-restricted expression and unique transcriptional non-responsiveness to classical MT inducers (zinc, cadmium, dexamethasone), demarcating it from MT-I/II.

    Evidence Molecular cloning, Northern blot, in vivo metal/hormone challenge in multiple species

    PMID:1464312 PMID:1631128

    Open questions at the time
    • Transcription factor(s) controlling brain-specific expression not identified
    • Whether non-responsiveness to metals is promoter-intrinsic not tested
  3. 1996 High

    MT3 knockout mice revealed an in vivo role in zinc-dependent neuromodulation, showing heightened kainate seizure sensitivity and localizing MT3 to hippocampal zinc-containing neurons rather than glia.

    Evidence MT3 knockout mouse, immunohistochemistry, kainate seizure model

    PMID:8751715

    Open questions at the time
    • Downstream zinc-dependent targets mediating seizure susceptibility unidentified
    • Contribution of MT3 to synaptic zinc release not directly measured
  4. 1998 High

    Spectroscopic characterization of recombinant MT3 domains defined the metal-thiolate cluster architecture—Cu4S9 preferentially in the beta-domain, M4S11 in the alpha-domain—establishing the structural basis for MT3's distinct metal-handling properties.

    Evidence Electronic absorption, CD, MCD, luminescence spectroscopy, 113Cd NMR on isolated alpha-domain and full-length protein

    PMID:10830840 PMID:12072966 PMID:9778374

    Open questions at the time
    • Full-length solution structure not determined at this stage
    • In vivo metal stoichiometry under physiological conditions uncertain
  5. 2001 High

    Domain-dissection experiments showed that MT3's beta-domain delivers zinc to mitochondrial respiratory complexes (inhibiting respiration) while its alpha-domain is the primary hydroxyl radical scavenger, establishing domain-specific functional duality.

    Evidence Mitochondrial import/respiration assay with isolated domains; EPR spin-trapping and neuronal/PC12 cytotoxicity assays

    PMID:11226237 PMID:11750760

    Open questions at the time
    • Physiological relevance of mitochondrial zinc delivery not confirmed in intact neurons
    • Relative contributions of the two domains to neuroprotection in vivo unknown
  6. 2002 High

    Cysteine thiolates were identified as the essential functional groups for MT3's antioxidant activity: NEM alkylation abolished protection against DNA damage and ROS, and ESR spin-trapping demonstrated MT3 scavenges hydroxyl radicals more efficiently than MT-I/II; noncooperative zinc binding and higher metal-transfer potential distinguished MT3 as a dynamic zinc buffer.

    Evidence Plasmid DNA damage assay with NEM modification; ESR spin-trapping; mass spectrometry and EDTA competition for metal binding kinetics

    PMID:11994011 PMID:12058024 PMID:12383939

    Open questions at the time
    • Structural basis for noncooperative binding not resolved
    • Whether dynamic zinc buffering occurs on synaptic timescales not tested
  7. 2003 High

    Epigenetic silencing of MT3 by CpG island hypermethylation was established as a mechanism for its loss in cancer, with 5-azacytidine treatment restoring expression in gastric carcinoma cells.

    Evidence Bisulfite sequencing, DHPLC methylation analysis, 5-azacytidine demethylation in cell lines and primary tumors

    PMID:12538345

    Open questions at the time
    • Whether methylation-mediated silencing is a driver or passenger event in tumorigenesis not determined
    • Methyl-CpG-binding proteins responsible not identified
  8. 2004 High

    MT3 was found to modulate cell death fate: its expression in renal cells shifted Cd2+-induced death from apoptosis to necrosis, revealing that MT3 does not simply protect against metal toxicity but actively redirects the mode of cell death.

    Evidence Stable MT3 transfection into HK-2 cells with Cd2+ challenge and apoptosis/necrosis quantification

    PMID:15129022

    Open questions at the time
    • Mechanism by which MT3 switches apoptosis to necrosis (e.g., zinc release, mitochondrial effects) not elucidated
    • Relevance to neuronal cell death not tested
  9. 2010 High

    MT3 was shown to regulate lysosomal integrity and autophagic flux through zinc dynamics: MT3-null cells had reduced LAMP-1/2 and lysosomal enzymes, while stress-induced zinc release from MT3 triggered lysosomal membrane permeabilization.

    Evidence MT3-null brain cell studies with lysosomal enzyme assays, LAMP protein quantification, and oxidative stress challenge

    PMID:20974010

    Open questions at the time
    • Identity of the zinc-sensitive lysosomal target(s) unknown
    • Whether lysosomal zinc release is the mechanism linking MT3 to necrotic death remains correlative
  10. 2011 High

    Zn7-MT3 was shown to suppress α-synuclein-Cu(II) redox toxicity through transmetallation: MT3's thiolates reduce Cu(II) to Cu(I), sequestering it in an oxygen-stable Cu(I)4-thiolate cluster and abolishing α-Syn oligomerization and ROS production.

    Evidence Stopped-flow kinetics, UV-vis/CD spectroscopy, mass spectrometry, ROS and aggregation assays with reconstituted α-Syn-Cu(II) complexes

    PMID:21320589

    Open questions at the time
    • In vivo relevance to Parkinson's disease pathology not demonstrated
    • Whether MT3 similarly detoxifies Cu-Aβ complexes in vivo remains unresolved
  11. 2016 High

    Thermodynamic characterization of Pb(II) binding to MT3 revealed entropically driven displacement of zinc, with three distinct binding populations and pH-stable Pb-MT3 complexes, establishing MT3 as a potential lead sequestrant.

    Evidence Isothermal titration calorimetry, EDTA chelation kinetics, CD spectroscopy on full-length and isolated domains

    PMID:26757944 PMID:30516222

    Open questions at the time
    • Physiological relevance of Pb sequestration in neurotoxicity not tested in cellular or animal models
    • Whether Pb binding disrupts MT3's zinc-buffering or antioxidant functions unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The in vivo mechanisms linking MT3's zinc-release dynamics to lysosomal regulation, the structural determinants of the apoptosis-to-necrosis switch, and the functional significance of MT3 transmetallation in neurodegenerative disease models remain unresolved.
  • No conditional knockout studies targeting MT3 in disease models
  • No high-resolution full-length structure of mixed Cu/Zn-loaded MT3
  • Direct in vivo evidence for MT3-mediated Cu-amyloid detoxification lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140313 molecular sequestering activity 5 GO:0008289 lipid binding 4 GO:0016209 antioxidant activity 4
Localization
GO:0005829 cytosol 2 GO:0005739 mitochondrion 1 GO:0005764 lysosome 1
Pathway
R-HSA-8953897 Cellular responses to stimuli 5 R-HSA-382551 Transport of small molecules 4 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 1
Partners
SNCA

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 MT3 (GIF) was purified from normal human brain as a 68 amino acid metallothionein-like protein with ~70% identity to MT-II, containing a unique 6 amino acid insert in the C-terminal region; it directly inhibited survival and neurite formation of cortical neurons in vitro, and was markedly reduced in a distinct subset of astrocytes in Alzheimer's disease cortex. Protein purification, amino acid sequencing, in vitro neuronal survival assay, immunohistochemistry Neuron High 1873033
1992 MT-III gene was cloned and shown to be brain-restricted in expression and to fail to respond to zinc, cadmium, dexamethasone, or bacterial endotoxin in vivo, distinguishing it from MT-I and MT-II; the gene is closely linked to other MT genes on human chromosome 16. Molecular cloning, Northern blot, in vivo metal/hormone challenge experiments Proceedings of the National Academy of Sciences of the United States of America High 1631128
1992 Molecular cloning of human GIF cDNA confirmed it as a new metallothionein family member with nervous-system-exclusive expression; recombinant GIF produced in E. coli inhibited the growth of neonatal rat cortical neurons, and GIF mRNA was drastically decreased in AD brains by Northern blot. cDNA cloning, recombinant protein expression in E. coli, neuronal growth inhibition assay, Northern blot The EMBO journal High 1464312
1994 Recombinant MT-III (but not MT-I) specifically inhibited survival of rat cortical neurons in culture when added to brain extract-supplemented cultures, confirming MT-III as a neuron-specific inhibitory factor; however, MT-III protein and mRNA levels were not significantly decreased in AD frontal cortex relative to controls in this study. Recombinant protein addition to neuronal cultures, Western blot, immunoassay Brain research High 7953645
1996 MT-III is expressed predominantly in zinc-containing neurons of the hippocampus (not glia), where it functions as a zinc buffer/regulator, and MT-III knockout mice show heightened sensitivity to kainate-induced seizures, establishing a role for MT-III in neuromodulation and zinc homeostasis in vivo. Immunohistochemistry, knockout mouse model, kainate seizure assay FASEB journal High 8751715
1998 Metal-thiolate cluster formation in the C-terminal alpha-domain of human GIF (residues 32-68) was characterized: with Cu(I), two air-sensitive Cu4S8-9 and Cu6S11 clusters form successively; with Zn(II) or Cd(II), a well-defined M4S11 cluster with tetrahedral coordination forms; 113Cd NMR revealed conformational flexibility of this domain. Electronic absorption spectroscopy, CD, MCD, luminescence spectroscopy, 113Cd NMR Biochemistry High 9778374
1998 MT-3 mRNA expression is not restricted to brain but is also present in rat testis, prostate, epididymis, tongue, ovary, uterus, stomach, heart, and seminal vesicles; prostatic MT-3 mRNA was decreased 75% by orchiectomy and restored by dihydrotestosterone treatment, establishing androgen-dependent regulation of MT-3 in the prostate. Northern blot, in situ hybridization, orchiectomy/DHT replacement experiments DNA and cell biology High 9655243
2000 Native GIF contains 4 Cu(I) and 3 Zn(II) ions in homometallic metal-thiolate clusters; stepwise Cu(I) incorporation into recombinant apo-MT-3 reveals cooperative formation of two Cu4S9 clusters (one per domain) and then Cu6S9 and Cu6S11 clusters in beta and alpha domains of fully metallated Cu12-MT-3; the Cu4 cluster preferentially forms in the N-terminal beta-domain. Electronic absorption, CD, MCD, luminescence spectroscopy, immunochemistry with domain-specific antibodies, limited tryptic digestion Journal of inorganic biochemistry High 10830840
2001 MT-3 (zinc metallothionein) imported into liver mitochondria inhibits respiration; this inhibition is caused specifically by the N-terminal beta-domain via zinc delivery to the electron transfer chain; the alpha-domain alone is inactive in this system, and carbamoylation of lysines attenuates import. Mitochondrial import assay, respiratory inhibition measurement, isolated domain experiments, chemical modification Proceedings of the National Academy of Sciences of the United States of America High 11226237
2001 The alpha-domain of GIF shows greater capacity to scavenge hydroxyl radicals and eliminate reactive oxygen species than the beta-domain, as demonstrated by EPR spin-trapping; both GIF and its domains protect neurons and PC12 cells from beta-amyloid 25-35 cytotoxicity. EPR spin-trapping, CytC-VitC radical-producing system, neuronal/PC12 cell cytotoxicity assay Biochimica et biophysica acta Medium 11750760
2002 MT-3 binds Zn2+ and Cd2+ noncooperatively (unlike MT-1/MT-2) and can accommodate more than 7 metal ions; the N-terminal beta-cluster accounts for heterogeneity of metalloforms and has higher metal-transfer potential than the beta-cluster of MT-2, suggesting MT-3 functions as a dynamic zinc buffer in zincergic neurons. Mass spectrometry, pH/stability studies, EDTA competition assay, ultrafiltration Biochemistry High 11994011
2002 MT-III protects against DNA strand breaks and deoxyribose degradation induced by Fe3+-NTA/H2O2 and scavenges superoxide anion; alkylation of sulfhydryl groups with N-ethylmaleimide abolishes the protective effect, demonstrating that the cysteine thiolate groups are the active moiety for ROS scavenging. Plasmid DNA single-strand break assay, deoxyribose degradation assay, xanthine/xanthine oxidase system, NEM chemical modification Biochimica et biophysica acta High 12383939
2002 The Cu4-thiolate cluster in MT-3 is located preferentially in the N-terminal beta-domain; using domain-specific antibodies combined with limited tryptic digestion of partially metal-occupied Cu4-MT-3, Cu4S9 cluster was assigned to the beta-domain containing 9 cysteines. Domain-specific antibody immunochemistry, limited tryptic digestion, CD and luminescence spectroscopy Journal of biological inorganic chemistry High 12072966
2002 Exogenous GIF (MT-III) prevents neurite extension of cortical neurons in early differentiation and protects differentiated neurons from high-oxygen-induced death; ESR spin-trapping showed GIF at 2-6 µM efficiently scavenges hydroxyl radicals (more effectively than MT-I+II at same concentration) but does not scavenge superoxide or NO; antisense knockdown of GIF promoted neuronal death under high oxygen. Cortical neuron culture, antisense S-oligonucleotide knockdown, ESR spin-trapping with Fenton reaction and H2O2 photolysis The Journal of biological chemistry High 12058024
2002 Stable transfection of human MT-III into GM00637 fibroblasts conferred significant resistance to H2O2-induced cytotoxicity, reduced ROS production, and protected against DNA damage, directly demonstrating MT-III antioxidant function in non-neural cells. Stable transfection, H2O2 challenge, LDH cytotoxicity, ROS measurement, comet assay FEBS letters Medium 12067712
2003 CpG island hypermethylation in intron 1 of the MT-3 gene silences its transcription in gastric carcinoma cell lines; treatment with 5-azacytidine (demethylating agent) restored MT-3 mRNA expression, establishing epigenetic regulation of MT-3 as a mechanism for its downregulation in cancer. Bisulfite sequencing, DHPLC methylation analysis, 5-azacytidine treatment, RT-PCR Carcinogenesis High 12538345
2004 MT-3 expression in HK-2 (human proximal tubule) cells (stably transfected) sensitized cells to Cd2+-induced cytotoxicity and shifted the mechanism of cell death from apoptosis (no MT-3) to necrosis (with MT-3), demonstrating that MT-3 controls the mode of cell death in response to heavy metal toxicity. Stable transfection of MT-3 into HK-2 cells, Cd2+ cytotoxicity assay, apoptosis/necrosis characterization Toxicological sciences High 15129022
2006 Solution structure of the alpha-domain (residues 32-68) of human MT-3 was determined by multinuclear/multidimensional NMR; the domain forms a metal-thiolate cluster similar in overall fold to mouse MT-3 but with a longer loop in the acidic hexapeptide insertion; backbone dynamics showed the beta-domain has similar internal motion to the alpha-domain though N-terminal residues are more flexible. Multinuclear multidimensional NMR spectroscopy, molecular dynamics simulated annealing FEBS letters High 16413543
2008 MT-III protects dopaminergic SH-SY5Y cells against 6-OHDA-induced oxidative stress through a mechanism involving PI3K and ERK kinase activation, Nrf2 nuclear translocation, and upregulation of heme oxygenase-1 (HO-1); inhibiting PI3K or ERK blocked MT-III-induced HO-1 expression and neuroprotection. Cell viability assay, ROS measurement, kinase inhibitor studies, Nrf2 nuclear fractionation, Western blot for HO-1 Toxicology and applied pharmacology Medium 18554677
2008 MT-3 mRNA expression in human adipocytes is dramatically (>600-fold) and rapidly (within 60 min) induced by hypoxia (1% O2) and by hypoxia mimetics (CoCl2, desferrioxamine, DMOG), indicating transcriptional regulation through HIF-1; MT-3 was also induced in preadipocytes and detected in human adipose tissue. PCR arrays, real-time RT-PCR, hypoxia mimetic treatment, preadipocyte cultures Biochemical and biophysical research communications Medium 18206644
2010 MT-3 regulates lysosomal function: in MT-3-null brain cells, lysosome-associated membrane proteins (LAMP-1/-2) and lysosomal enzyme levels are reduced with decreased autophagic flux; under acute oxidative stress, zinc released from MT-3 accumulates in autolysosomes and triggers lysosomal membrane permeabilization leading to cell death; absence of MT-3 reduces zinc-mediated lysosomal damage and decreases acute cell death. MT-3 null cell studies, lysosomal enzyme assays, LAMP protein expression, autophagic flux measurement, oxidative stress challenge Molecular brain High 20974010
2011 Zn7-MT-3 removes Cu(II) from the α-synuclein-Cu(II) complex through reduction of Cu(II) by thiolate ligands, forming Cu(I)4Zn4MT-3 with an unusual oxygen-stable Cu(I)4-thiolate cluster; this mechanism abolishes α-Syn catalytic oxidase activity, prevents α-Syn oligomerization, hydroxyl radical production, and dopamine oxidation. UV-vis and CD spectroscopy, stopped-flow kinetics, mass spectrometry, ROS detection, α-Syn aggregation assay Free radical biology & medicine High 21320589
2014 MT3 promoter hypermethylation silences expression in pediatric AML cell lines and patient samples; lentiviral MT3 overexpression in AML cells inhibited proliferation and induced apoptosis; PCR array analysis identified FOXO1 as dysregulated downstream of MT3 overexpression, suggesting FOXO1 as part of the MT3-mediated pro-apoptotic pathway. MSP and bisulfite genomic sequencing, lentiviral overexpression, Annexin V apoptosis assay, RT-PCR array Journal of translational medicine Medium 24962166
2016 Isothermal titration calorimetry showed Pb2+ binding to Zn7MT-3 displaces each zinc ion with similar ΔG and ΔH; EDTA chelation studies revealed both Zn and Pb are extracted in a tri-phasic process indicating three binding populations with different thermodynamics; metal binding is entropically favored with an enthalpic penalty reflecting cysteine deprotonation upon thiolate ligation. Isothermal titration calorimetry (ITC), EDTA chelation, CD spectroscopy Metallomics High 26757944
2017 Comprehensive review and experimental synthesis established that MT-3 possesses distinct Cu/Zn metal-thiolate cluster properties compared to MT-1/MT-2; specifically, Zn7MT-3 (but not MT-1/MT-2) protects neuronal cells from toxicity of Cu(II)-bound amyloids (Aβ, α-Syn) by transmetallation, and the unique acidic hexapeptide insert in the C-terminal domain and the N-terminal extension are structural determinants of its distinct biological activity. Review integrating structural (NMR, spectroscopy) and functional (cell toxicity) data; domain mutagenesis context International journal of molecular sciences Medium 28538697
2019 Pb(II) binding to full-length MT3 is relatively unaffected by pH (stable), whereas isolated alpha and beta fragments interact with Pb(II) in a pH-sensitive manner; mass spectrometry revealed Pb-MT3 complexes persist long-term with intact protein but Pb is eventually released from isolated fragments; Zn(II) displacement by Pb(II) is thermodynamically favorable in both intact MT3 and isolated domains. Spectroscopy, mass spectrometry, isothermal titration calorimetry, pH-dependent binding studies Metallomics High 30516222
2020 miR-325-3p directly targets the MT3 3'UTR (confirmed by dual-luciferase reporter assay); MT3 overexpression in bladder cancer T24 cells promotes proliferation, invasion, migration, and EMT (increased MMP9, decreased E-cadherin); miR-325-3p mimics suppress these effects by reducing MT3 levels. Dual-luciferase reporter assay, transwell invasion/migration assay, CCK-8 proliferation assay, Western blot for EMT markers Medical science monitor Medium 32512576

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1991 The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein. Neuron 622 1873033
1992 MT-III, a brain-specific member of the metallothionein gene family. Proceedings of the National Academy of Sciences of the United States of America 544 1631128
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2000 Identification of the melatonin-binding site MT3 as the quinone reductase 2. The Journal of biological chemistry 438 10913150
2020 A GRF-GIF chimeric protein improves the regeneration efficiency of transgenic plants. Nature biotechnology 355 33046875
2014 Post-transcriptional control of GRF transcription factors by microRNA miR396 and GIF co-activator affects leaf size and longevity. The Plant journal : for cell and molecular biology 235 24888433
2001 Zinc metallothionein imported into liver mitochondria modulates respiration. Proceedings of the National Academy of Sciences of the United States of America 204 11226237
2010 Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes. Molecular brain 180 20974010
1996 The functional significance of brain metallothioneins. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 164 8751715
1992 Molecular cloning of human growth inhibitory factor cDNA and its down-regulation in Alzheimer's disease. The EMBO journal 163 1464312
2003 HIV-1 Tat reprograms immature dendritic cells to express chemoattractants for activated T cells and macrophages. Nature medicine 161 12539042
1994 Enhanced neurotrophic activity in Alzheimer's disease cortex is not associated with down-regulation of metallothionein-III (GIF). Brain research 159 7953645
2009 An unusually stable G-quadruplex within the 5'-UTR of the MT3 matrix metalloproteinase mRNA represses translation in eukaryotic cells. Biochemistry 129 19397366
2003 Differential inhibition of membrane type 3 (MT3)-matrix metalloproteinase (MMP) and MT1-MMP by tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3 rgulates pro-MMP-2 activation. The Journal of biological chemistry 118 14681236
2012 The porphyrin TmPyP4 unfolds the extremely stable G-quadruplex in MT3-MMP mRNA and alleviates its repressive effect to enhance translation in eukaryotic cells. Nucleic acids research 117 22266651
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
2001 Involvement of melatonin MT(3) receptors in the regulation of intraocular pressure in rabbits. European journal of pharmacology 102 11290376
1998 Expression of the gene encoding metallothionein-3 in organs of the reproductive system. DNA and cell biology 102 9655243
2002 Growth inhibitory factor prevents neurite extension and the death of cortical neurons caused by high oxygen exposure through hydroxyl radical scavenging. The Journal of biological chemistry 101 12058024
1997 Expression of three membrane-type matrix metalloproteinases (MT-MMPs) in rat vascular smooth muscle cells and characterization of MT3-MMPs with and without transmembrane domain. The Journal of biological chemistry 101 9092507
2007 Melatonin as a naturally occurring co-substrate of quinone reductase-2, the putative MT3 melatonin membrane receptor: hypothesis and significance. Journal of pineal research 97 17910598
2010 Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells. Molecular & cellular proteomics : MCP 93 21044950
2014 An RNA-seq method for defining endoribonuclease cleavage specificity identifies dual rRNA substrates for toxin MazF-mt3. Nature communications 87 24709835
2003 Co-recycling of MT1-MMP and MT3-MMP through the trans-Golgi network. Identification of DKV582 as a recycling signal. The Journal of biological chemistry 87 14665622
2008 The mRNA interferases, MazF-mt3 and MazF-mt7 from Mycobacterium tuberculosis target unique pentad sequences in single-stranded RNA. Molecular microbiology 86 18485066
2005 Characterization of the melatoninergic MT3 binding site on the NRH:quinone oxidoreductase 2 enzyme. Biochemical pharmacology 85 16293234
2003 Ocular hypotensive effects of melatonin receptor agonists in the rabbit: further evidence for an MT3 receptor. British journal of pharmacology 85 12642384
1999 Expression of MT-3 protein in the human kidney. Toxicology letters 83 10355541
2017 Mammalian Metallothionein-3: New Functional and Structural Insights. International journal of molecular sciences 80 28538697
1984 Molecular localization of human class II MT2 and MT3 determinants. The Journal of experimental medicine 79 6206179
2002 Brain-specific metallothionein-3 has higher metal-binding capacity than ubiquitous metallothioneins and binds metals noncooperatively. Biochemistry 75 11994011
2019 Biological roles and an evolutionary sketch of the GRF-GIF transcriptional complex in plants. BMB reports 74 30885290
2008 PCR arrays identify metallothionein-3 as a highly hypoxia-inducible gene in human adipocytes. Biochemical and biophysical research communications 71 18206644
2004 Effect of 5-MCA-NAT, a putative melatonin MT3 receptor agonist, on intraocular pressure in glaucomatous monkey eyes. Journal of glaucoma 71 15354076
1997 Expression of MT-3 mRNA in human kidney, proximal tubule cell cultures, and renal cell carcinoma. Toxicology letters 71 9295238
2006 Solution structure and dynamics of human metallothionein-3 (MT-3). FEBS letters 66 16413543
1996 Rat striatal muscarinic receptors coupled to the inhibition of adenylyl cyclase activity: potent block by the selective m4 ligand muscarinic toxin 3 (MT3). British journal of pharmacology 63 8735628
1997 Regulation of metallothionein-III (GIF) mRNA in the brain of patients with Alzheimer disease is not impaired. Molecular and chemical neuropathology 62 9437661
2004 Involvement of membrane-type matrix metalloproteinases (MT-MMPs) in capillary tube formation by human endometrial microvascular endothelial cells: role of MT3-MMP. The Journal of clinical endocrinology and metabolism 60 15531549
1998 Metal-thiolate clusters in the C-terminal domain of human neuronal growth inhibitory factor (GIF). Biochemistry 58 9778374
2008 Metallothionein-III protects against 6-hydroxydopamine-induced oxidative stress by increasing expression of heme oxygenase-1 in a PI3K and ERK/Nrf2-dependent manner. Toxicology and applied pharmacology 57 18554677
2006 Increase in fluidity in the membrane of MT3 breast cancer cells correlates with enhanced cell adhesion in vitro and increased lung metastasis in NOD/SCID mice. Archives of biochemistry and biophysics 57 17222386
2004 Sequence comparison of human and mouse genes reveals a homologous block structure in the promoter regions. Genome research 57 15342556
1999 Metallothionein isoform 3 expression in the human prostate and cancer-derived cell lines. The Prostate 57 10517878
2012 MT3 melatonin binding site, MT1 and MT2 melatonin receptors are present in oocyte, but only MT1 is present in bovine blastocyst produced in vitro. Reproductive biology and endocrinology : RB&E 56 23207065
2004 Organs from mice deleted for NRH:quinone oxidoreductase 2 are deprived of the melatonin binding site MT3. FEBS letters 56 15581627
2008 Differential expression of metallothioneins (MTs) 1, 2, and 3 in response to zinc treatment in human prostate normal and malignant cells and tissues. Molecular cancer 55 18208603
2006 New ligands at the melatonin binding site MT(3). European journal of medicinal chemistry 54 16414149
1985 Molecular characterization of MT3 antigens by two-dimensional gel electrophoresis, NH2-terminal amino acid sequence analysis, and southern blot analysis. Proceedings of the National Academy of Sciences of the United States of America 54 2582424
2018 Is There Sufficient Evidence that the Melatonin Binding Site MT Is Quinone Reductase 2? The Journal of pharmacology and experimental therapeutics 53 30389722
2002 Protective effect of metallothionein-III on DNA damage in response to reactive oxygen species. Biochimica et biophysica acta 52 12383939
2011 Redox activity of α-synuclein-Cu is silenced by Zn₇-metallothionein-3. Free radical biology & medicine 51 21320589
2011 A new perspective in Oral health: potential importance and actions of melatonin receptors MT1, MT2, MT3, and RZR/ROR in the oral cavity. Archives of oral biology 51 21459362
1984 Antigen-specific HLA-restricted human T-cell lines. I. An MT3-like restriction determinant distinct from HLA-DR. Immunogenetics 48 6198272
2000 Posttranslational modification of the glycosylation inhibiting factor (GIF) gene product generates bioactive GIF. Proceedings of the National Academy of Sciences of the United States of America 47 11069294
2020 GRF-GIF Chimeras Boost Plant Regeneration. Trends in plant science 46 33349565
2018 GIF Transcriptional Coregulators Control Root Meristem Homeostasis. The Plant cell 46 29352064
1995 Expression of growth inhibitory factor (GIF) in normal and injured rat brains. Neurochemistry international 46 7655350
2011 The M4 muscarinic antagonist MT-3 inhibits myopia in chick: evidence for site of action. Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians (Optometrists) 45 21539592
2006 Identification of intrahepatic cholangiocarcinoma related genes by comparison with normal liver tissues using expressed sequence tags. Biochemical and biophysical research communications 45 16712791
2002 Transient induction of metallothionein isoform 3 (MT-3), c-fos, c-jun and c-myc in human proximal tubule cells exposed to cadmium. Toxicology letters 44 11738272
2017 Participation of MT3 melatonin receptors in the synergistic effect of melatonin on cytotoxic and apoptotic actions evoked by chemotherapeutics. Cancer chemotherapy and pharmacology 42 28956121
2015 Arachidonic acid promotes skin wound healing through induction of human MSC migration by MT3-MMP-mediated fibronectin degradation. Cell death & disease 42 25950480
2000 Functional characterization of MT3-MMP in transfected MDCK cells: progelatinase A activation and tubulogenesis in 3-D collagen lattice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 42 11099475
2005 Screening the metallothionein III gene in sporadic amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases 41 16036436
1995 Modulation of metallothionein-III mRNA content and growth rate of rat C6-glial cells by transfection with human 5-HT1D receptor genes. Biochemical and biophysical research communications 41 7677777
2013 Extracellular HIV-1 viral protein R affects astrocytic glyceraldehyde 3-phosphate dehydrogenase activity and neuronal survival. Journal of neurovirology 40 23728617
2003 Hypermethylation of metallothionein-3 CpG island in gastric carcinoma. Carcinogenesis 40 12538345
1992 Characterization of two human mammary carcinomas, MT-1 and MT-3, suitable for in vivo testing of ether lipids and their derivatives. Breast cancer research and treatment 40 1446057
2004 Expression of metallothionein isoform 3 (MT-3) determines the choice between apoptotic or necrotic cell death in Cd+2-exposed human proximal tubule cells. Toxicological sciences : an official journal of the Society of Toxicology 38 15129022
2002 A distinct Cu(4)-thiolate cluster of human metallothionein-3 is located in the N-terminal domain. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 38 12072966
1986 Structural relationships between the DR beta 1 and DR beta 2 subunits in DR4, 7, and w9 haplotypes and the DRw53 (MT3) specificity. Journal of immunology (Baltimore, Md. : 1950) 38 2424991
2002 Overexpression of human metallothionein-III prevents hydrogen peroxide-induced oxidative stress in human fibroblasts. FEBS letters 37 12067712
1984 Biochemical and functional evidence that an MT3 supertypic determinant defined by a monoclonal antibody is carried on the DR molecule on HLA-DR7 cell lines. Journal of immunology (Baltimore, Md. : 1950) 37 6208273
2011 Membrane-type-3 matrix metalloproteinase (MT3-MMP) functions as a matrix composition-dependent effector of melanoma cell invasion. PloS one 36 22164270
2004 Cysteine-dependent immune regulation by TRX and MIF/GIF family proteins. Immunology letters 36 15081538
1998 Expression of the membrane-type 3 matrix metalloproteinase (MT3-MMP) in human brain tissues. Acta neuropathologica 35 9796998
2016 Thermodynamics of Pb(ii) and Zn(ii) binding to MT-3, a neurologically important metallothionein. Metallomics : integrated biometal science 33 26757944
2014 Metallothionein III (MT3) is a putative tumor suppressor gene that is frequently inactivated in pediatric acute myeloid leukemia by promoter hypermethylation. Journal of translational medicine 33 24962166
2012 Barley metallothioneins: MT3 and MT4 are localized in the grain aleurone layer and show differential zinc binding. Plant physiology 33 22582132
2001 Coordinate expression of membrane type-matrix metalloproteinases-2 and 3 (MT2-MMP and MT3-MMP) and matrix metalloproteinase-2 (MMP-2) in primary and metastatic melanoma cells. European journal of dermatology : EJD 32 11525948
2017 A new role of the membrane-type matrix metalloproteinase 16 (MMP16/MT3-MMP) in neural crest cell migration. The International journal of developmental biology 29 28621422
1998 Brain injury and growth inhibitory factor (GIF)--a minireview. Neurochemical research 28 9482244
2023 GRF-GIF chimeric proteins enhance in vitro regeneration and Agrobacterium-mediated transformation efficiencies of lettuce (Lactuca spp.). Plant cell reports 27 36695930
2008 MT3/QR2 melatonin binding site does not use melatonin as a substrate or a co-substrate. Journal of pineal research 27 18826489
2010 Molecular and cellular pharmacological properties of 5-methoxycarbonylamino-N-acetyltryptamine (MCA-NAT): a nonspecific MT3 ligand. Journal of pineal research 26 20210850
2004 Expression analysis of buckwheat (Fagopyrum esculentum Moench) metallothionein-like gene (MT3) under different stress and physiological conditions. Journal of plant physiology 26 15266722
2005 Growth inhibitory factor (GIF) can protect from brain damage due to stab wounds in rat brain. Neuroscience letters 24 16314047
1996 Patterns of growth inhibitory factor (GIF) and glial fibrillary acidic protein relative level changes differ following left middle cerebral artery occlusion in rats. Brain research 24 8869568
2004 A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency. Human mutation 23 14695536
2014 Metallothionein-3 (MT-3) in the human adrenal cortex and its disorders. Endocrine pathology 22 24242700
2009 Conservation and variation of the parapoxvirus GM-CSF-inhibitory factor (GIF) proteins. The Journal of general virology 22 19264672
1983 Identification of the MT3 molecule using two-dimensional gel electrophoresis and alloantisera. Immunogenetics 22 6197369
1991 Antibody MT3 is reactive with a novel exon B-associated 190-kDa sialic acid-dependent epitope of the leukocyte common antigen complex. Journal of immunology (Baltimore, Md. : 1950) 21 1711075
2024 Use of GRF-GIF chimeras and a ternary vector system to improve maize (Zea mays L.) transformation frequency. The Plant journal : for cell and molecular biology 20 38923048
2013 Gastric intrinsic factor deficiency with combined GIF heterozygous mutations and FUT2 secretor variant. Biochimie 20 23402911
2017 Developmental processes and responses to hormonal stimuli in tea plant (Camellia sinensis) leaves are controlled by GRF and GIF gene families. Functional & integrative genomics 19 28236273
2007 Overexpression of MT3-MMP in hepatocellular carcinoma correlates with capsular invasion. Hepato-gastroenterology 19 17419254
2001 Different protective roles in vitro of alpha- and beta-domains of growth inhibitory factor (GIF) on neuron injuries caused by oxygen free radicals. Biochimica et biophysica acta 19 11750760
1984 Molecular identifications of HLA-DR4, MT3, and TB21 antigens on HLA-DR4 homozygous B cell lines. Journal of immunology (Baltimore, Md. : 1950) 19 6418807
2022 The Rice miR396-GRF-GIF-SWI/SNF Module: A Player in GA Signaling. Frontiers in plant science 18 35087553
2012 Current status and limitations of the newly developed endocytoscope GIF-Y0002 with reference to its diagnostic performance for common esophageal lesions. Journal of digestive diseases 18 22788924
1998 Stimulatory effects of 4-methylcatechol, dopamine and levodopa on the expression of metallothionein-III (GIF) mRNA in immortalized mouse brain glial cells (VR-2g). Brain research 17 9593981
1987 Establishment and characterization of a human IgA-kappa-secreting plasma cell line (MT3). International journal of cancer 17 3114153
2022 Identification and exploration of the GRF and GIF families in maize and foxtail millet. Physiology and molecular biology of plants : an international journal of functional plant biology 16 36387975
2015 Melatonin inhibits granulocyte adhesion to ICAM via MT3/QR2 and MT2 receptors. International immunology 16 26031343
2000 Metal-thiolate clusters in neuronal growth inhibitory factor (GIF). Journal of inorganic biochemistry 16 10830840
2023 Whole-genome identification and expression profiling of growth-regulating factor (GRF) and GRF-interacting factor (GIF) gene families in Panax ginseng. BMC genomics 15 37328802
2016 Structural basis of GM-CSF and IL-2 sequestration by the viral decoy receptor GIF. Nature communications 15 27819269
2010 Prospective replacement of magnifying endoscopy by a newly developed endocytoscope, the 'GIF-Y0002'. Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus 15 20545974
2018 Ag-NPs induce apoptosis, mitochondrial damages and MT3/OSGIN2 expression changes in an in vitro model of human dental-pulp-stem-cells-derived neurons. Neurotoxicology 14 29698629
1986 A human monoclonal antibody to an HLA-DRw53 (MT3)-like epitope on class II antigens. Tissue antigens 14 2431513
2019 Pb(ii) binding to the brain specific mammalian metallothionein isoform MT3 and its isolated αMT3 and βMT3 domains. Metallomics : integrated biometal science 13 30516222
2017 Expression and immunolocalization of metallothioneins MT1, MT2 and MT3 in rat nephron. Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS) 13 29413112
2006 Facilitatory effect of the intra-hippocampal pre-test administration of MT3 in the inhibitory avoidance task. Behavioural brain research 13 17182118
1984 Identification of three class II antigens, DR7, MB2, and MT3, from a homozygous human cell line. Human immunology 13 6199337
2017 MT3-MMP Promotes Excitatory Synapse Formation by Promoting Nogo-66 Receptor Ectodomain Shedding. The Journal of neuroscience : the official journal of the Society for Neuroscience 12 29196321
2009 Inhibition of pulmonary metastasis in a human MT3 breast cancer xenograft model by dual liposomes preventing intravasal fibrin clot formation. Breast cancer research and treatment 12 19548083
2014 The Muscarinic Antagonist MT3 Distinguishes Between Form Deprivation- and Negative Lens-Induced Myopia in Chicks. Current eye research 11 25310574
1984 The MT3 specificity resides on a novel human class II antigen distinct from the HLA-DR antigen and DC-like antigen. Immunogenetics 11 6205988
2024 Genome-wide identification and expression profiling of growth‑regulating factor (GRF) and GRF‑interacting factor (GIF) gene families in chickpea and pigeonpea. Scientific reports 10 39060385
2022 Bioreduction and bioremoval of hexavalent chromium by genetically engineered strains (Escherichia coli MT2A and Escherichia coli MT3). World journal of microbiology & biotechnology 10 35075546
2020 miR-325-3p Overexpression Inhibits Proliferation and Metastasis of Bladder Cancer Cells by Regulating MT3. Medical science monitor : international medical journal of experimental and clinical research 10 32512576
2018 Structural Basis for the Interaction and Processing of β-Lactam Antibiotics by l,d-Transpeptidase 3 (LdtMt3) from Mycobacterium tuberculosis. ACS infectious diseases 10 30556998
2011 Design and synthesis of naphthalenic derivatives as new ligands at the melatonin binding site MT3. European journal of medicinal chemistry 10 21377769
2007 [Melatonin binding site MT3 is QR2: state of the art]. Journal de la Societe de biologie 10 17762829
2006 Cloning and developmental characterization of Xenopus laevis membrane type-3 matrix metalloproteinase (MT3-MMP). Biochemistry and cell biology = Biochimie et biologie cellulaire 10 16609697
1984 Identification of the MT3 molecule from HLA-DR4, 7, and w9 homozygous cell lines. Journal of immunology (Baltimore, Md. : 1950) 10 6436378