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Gene Review

MT3  -  metallothionein 3

Homo sapiens

Synonyms: GIF, GIFB, GRIF, Growth inhibitory factor, MT-3, ...
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Disease relevance of MT3

  • The gain in MT3 expression when cells were grown as heterotransplants was also shown to occur for the MCF-7, T-47D, Hs 578t, MDA-MB-231 breast cancer, and the PC-3 prostate cancer cell lines [1].
  • In contrast, 103 of 107 (96.26%) high-grade urothelial cancers and 17 of 17 (100%) specimens of carcinoma in situ stained positive for the MT3 protein [1].
  • An isomer of MTs, MT3, of particular interest, was originally discovered as a growth inhibitory factor, and has been found to be markedly reduced in the brain of patients with Alzheimer's disease and several other neurodegenerative diseases [2].
  • The ability of accessory cells to present mumps antigen in the context of this supertypic restriction determinant was blocked by a monoclonal antibody specific for MT3 [3].
  • In SCID mice, the concentrations of human immunoglobulin G, antithyroglobulin and antithyroperoxidase antibodies in sera were not significantly changed by injecting MT3 [4].
  • MT3 seems to accumulate in the cytoplasm of adrenocortical carcinoma cells, in contrast to benign cells of aldosterone-producing adenomas, which present MT3 in the nuclei [5].

Psychiatry related information on MT3

  • MT3, also known as Growth Inhibitory Factor (GIF), is postulated to inhibit neuron outgrowth in Alzheimer's disease [6].
  • A quantitative Western blot analysis also revealed that MT-I/II protein accumulated in CJD brain with a short disease duration, whereas MT3 in CJD brain with a long disease duration was statistically significantly reduced in comparison to the normal brains [7].

High impact information on MT3


Chemical compound and disease context of MT3


Biological context of MT3

  • MT3 shows apparently different properties and function from MT1 even though they have 70% sequence homology [14].
  • The results showed that transient overexpression of human MT1A, MT2 and MT3 genes dynamically affected cell viability, and the effect was influenced by zinc and cadmium ions [15].
  • However, the reaction of the E23K mutant with SNOC exhibited biphasic kinetics and the mutant protein released zinc ions much faster than MT3 in the initial step, while MT3 exhibited single kinetic process [16].
  • MT3 fulfills unique biological roles in homeostasis of the central nervous system and in the etiology of neuropathological disorders [2].
  • Protective effect of MT3 on DNA damage in response to reactive oxygen species [17].

Anatomical context of MT3

  • Molecular identifications of HLA-DR4, MT3, and TB21 antigens on HLA-DR4 homozygous B cell lines [18].
  • Furthermore, when comparisons were possible, the MT3 pharmacological characteristics were similar to those described in the literature for hamster brain and testis [19].
  • Antigen-specific HLA-restricted human T-cell lines. I. An MT3-like restriction determinant distinct from HLA-DR [3].
  • MT3 was added to cultured peripheral blood mononuclear cells (PBMC) from patients with AITD and was additionally injected into severe combined immunodeficient (SCID) mice to which Graves' thyroid cells and intrathyroidal lymphocytes were engrafted [4].
  • Because MT3 is also expressed by the normal and ALS spinal cord, it is a central nervous system-specific and not only a brain-specific protein [20].

Associations of MT3 with chemical compounds

  • A series of MT3 variants around the EAAEAE hexapeptide have been prepared by site-directed mutagenesis and their properties and reactivity towards pH, EDTA and DTNB have been studied [14].
  • We suggest the hydroxyl group in human GIF may help stabilize the biologically active conformation [6].
  • MT3 was also able to efficiently remove the superoxide anion, which was generated from the xanthine/xanthine oxidase system [17].
  • In this study, we show that MT3 is able to protect against the DNA damage induced by ferric ion-nitrilotriacetic acid and H(2)O(2), and that this protective effect is inhibited by the alkylation of the sulfhydryl groups of MT-III by treatment with EDTA and N-ethylmaleimide [17].
  • Results showed that apo-MT3 and apo-MT2 have almost equal helical content (approximately 10%) in aqueous buffer, but that MT- had slightly higher tendency to form alpha-helical secondary structure in TFE-water mixtures [21].

Physical interactions of MT3

  • Results demonstrate that MT3 binds Zn2+ and Cd2+ ions more weakly than MT2 but expresses higher metal-binding capacity and plasticity [21].

Regulatory relationships of MT3

  • Using an 8-oxoguanine DNA glycosylase (OGG1)-specific siRNAs, we also found that MT3 expression resulted in the suppression of the gamma-radiation-induced 8-oxoG accumulation and mutation in the OGG1-depleted cells [22].
  • MT3 stimulated proliferation of PBMC when cultured for 2 to 3 days in patients with Hashimoto's thyroiditis (HT) and Graves' disease (GD) and in normal controls (NC) [4].

Analytical, diagnostic and therapeutic context of MT3


  1. Enhanced expression of metallothionein isoform 3 protein in tumor heterotransplants derived from as+3- and cd+2-transformed human urothelial cells. Zhou, X.D., Sens, M.A., Garrett, S.H., Somji, S., Park, S., Gurel, V., Sens, D.A. Toxicol. Sci. (2006) [Pubmed]
  2. Localization, regulation, and function of metallothionein-III/growth inhibitory factor in the brain. Sogawa, C.A., Asanuma, M., Sogawa, N., Miyazaki, I., Nakanishi, T., Furuta, H., Ogawa, N. Acta Med. Okayama (2001) [Pubmed]
  3. Antigen-specific HLA-restricted human T-cell lines. I. An MT3-like restriction determinant distinct from HLA-DR. Ball, E.J., Stastny, P. Immunogenetics (1984) [Pubmed]
  4. Effects of monoclonal antibody against CD45RB on peripheral blood mononuclear cell proliferation and on HLA-DR and adhesion molecule expression on thyrocytes of patients with autoimmune thyroid disease. Nishikawa, M., Mukuta, T., Arreaza, G., Resetkova, E., Poppema, S., Tamai, H., Volpé, R., Lazarovits, A.I. Thyroid (1995) [Pubmed]
  5. Metallothionein-3 (MT-3) in the human adrenal cortex and its disorders. Felizola, S.J., Nakamura, Y., Arata, Y., Ise, K., Satoh, F., Rainey, W.E., Midorikawa, S., Suzuki, S., Sasano, H. Endocr. Pathol. (2014) [Pubmed]
  6. The role of Thr5 in human neuron growth inhibitory factor. Cai, B., Zheng, Q., Teng, X.C., Chen, D., Wang, Y., Wang, K.Q., Zhou, G.M., Xie, Y., Zhang, M.J., Sun, H.Z., Huang, Z.X. J. Biol. Inorg. Chem. (2006) [Pubmed]
  7. Differential expression of metallothioneins in human prion diseases. Kawashima, T., Doh-ura, K., Torisu, M., Uchida, Y., Furuta, A., Iwaki, T. Dementia and geriatric cognitive disorders. (2000) [Pubmed]
  8. IgE-binding factors and regulation of the IgE antibody response. Ishizaka, K. Annu. Rev. Immunol. (1988) [Pubmed]
  9. Molecular localization of human class II MT2 and MT3 determinants. Hurley, C.K., Giles, R.C., Nunez, G., DeMars, R., Nadler, L., Winchester, R., Stastny, P., Capra, J.D. J. Exp. Med. (1984) [Pubmed]
  10. The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein. Uchida, Y., Takio, K., Titani, K., Ihara, Y., Tomonaga, M. Neuron (1991) [Pubmed]
  11. Hypermethylation of metallothionein-3 CpG island in gastric carcinoma. Deng, D., El-Rifai, W., Ji, J., Zhu, B., Trampont, P., Li, J., Smith, M.F., Powel, S.M. Carcinogenesis (2003) [Pubmed]
  12. Bioactivity of metallothionein-3 correlates with its novel beta domain sequence rather than metal binding properties. Sewell, A.K., Jensen, L.T., Erickson, J.C., Palmiter, R.D., Winge, D.R. Biochemistry (1995) [Pubmed]
  13. Interactions of growth inhibitory factor with hydroxyl and superoxide radicals. Shi, Y., Wang, W., Mo, J., Du, L., Yao, S., Tang, W. Biometals (2003) [Pubmed]
  14. The effect of the EAAEAE insert on the property of human metallothionein-3. Zheng, Q., Yang, W.M., Yu, W.H., Cai, B., Teng, X.C., Xie, Y., Sun, H.Z., Zhang, M.J., Huang, Z.X. Protein Eng. (2003) [Pubmed]
  15. Effect of metallothionein on cell viability and its interactions with cadmium and zinc in HEK293 cells. Li, J., Liu, Y., Ru, B. Cell Biol. Int. (2005) [Pubmed]
  16. Mutation at Glu23 eliminates the neuron growth inhibitory activity of human metallothionein-3. Ding, Z.C., Teng, X.C., Cai, B., Wang, H., Zheng, Q., Wang, Y., Zhou, G.M., Zhang, M.J., Wu, H.M., Sun, H.Z., Huang, Z.X. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  17. Protective effect of metallothionein-III on DNA damage in response to reactive oxygen species. You, H.J., Oh, D.H., Choi, C.Y., Lee, D.G., Hahm, K.S., Moon, A.R., Jeong, H.G. Biochim. Biophys. Acta (2002) [Pubmed]
  18. Molecular identifications of HLA-DR4, MT3, and TB21 antigens on HLA-DR4 homozygous B cell lines. Maeda, H., Hirata, R. J. Immunol. (1984) [Pubmed]
  19. Characterization of 2-[125I]iodomelatonin binding sites in Syrian hamster peripheral organs. Paul, P., Lahaye, C., Delagrange, P., Nicolas, J.P., Canet, E., Boutin, J.A. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  20. Expression of different metallothionein messenger ribonucleic acids in motor cortex, spinal cord and liver from patients with amyotrophic lateral sclerosis. Blaauwgeers, H.G., Anwar Chand, M., van den Berg, F.M., Vianney de Jong, J.M., Troost, D. J. Neurol. Sci. (1996) [Pubmed]
  21. Metal binding of metallothionein-3 versus metallothionein-2: lower affinity and higher plasticity. Palumaa, P., Tammiste, I., Kruusel, K., Kangur, L., Jörnvall, H., Sillard, R. Biochim. Biophys. Acta (2005) [Pubmed]
  22. Metallothionein-III prevents gamma-ray-induced 8-oxoguanine accumulation in normal and hOGG1-depleted cells. Jeong, H.G., Youn, C.K., Cho, H.J., Kim, S.H., Kim, M.H., Kim, H.B., Chang, I.Y., Lee, Y.S., Chung, M.H., You, H.J. J. Biol. Chem. (2004) [Pubmed]
  23. Molecular characterization of MT3 antigens by two-dimensional gel electrophoresis, NH2-terminal amino acid sequence analysis, and southern blot analysis. Sorrentino, R., Lillie, J., Strominger, J.L. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
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