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Gene Review

MT2A  -  metallothionein 2A

Homo sapiens

Synonyms: CES1, MT-2, MT-II, MT2, Metallothionein-2, ...
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Disease relevance of MT2A


Psychiatry related information on MT2A


High impact information on MT2A

  • MTs exist in several molecular forms (MT-I, MT-II) and are encoded by a multi-gene family containing at least 14 closely related genes and pseudogenes [11].
  • We now show that the rate of transcription of MT2A is the same on treatment with interferon or dexamethasone, but that the mRNA accumulates much faster with dexamethasone, indicating that post-transcriptional events are important in the latter case [12].
  • Furthermore, comparison of regions upstream of the MT2A gene, two HLA genes and one HLA class II gene reveals a homologous sequence of approximately 30 base pairs (bp) which may be involved in regulating transcription of interferon-induced genes [12].
  • We now show that IFN-alpha treatment results in a three- to fivefold increase in the transcription of MT2 and HLA class I genes in human T98G neuroblastoma cells [12].
  • One is a functional metallothionein-II gene, the other a pseudogene, lacking introns, terminating in a poly(A) tail and flanked by two direct repeats [13].

Chemical compound and disease context of MT2A

  • We previously demonstrated that Actinomycin D (ActD) enhanced HIV-1 replication in the MT-2 cell, a human T-cell leukemia virus type-1-infected cell line [14].
  • Treatment of the human metastatic breast cancer cell line MT-2 with oltipraz results in a concentration-dependent increase in the activity of the calcium-dependent calpain, as measured towards the BOC-LM-CMAC fluorescent substrate [15].
  • Conditioned media from cultures of human T-cell lymphotropic virus type I-infected cell line (MT-2) as well as peripheral lymphocytes from a hypercalcemic ATLL patient stimulated cyclic AMP production in osteoblast-like rat osteogenic sarcoma cells (UMR 106) and bone resportion in organ cultures of fetal mouse calvaria [16].
  • An HIV-1 strain carrying a shorter form of the transmembrane glycoprotein (TM) with a mobility of 32 kD, named KB-1, was isolated from a Japanese male hemophiliac by coculture of his peripheral blood mononuclear cells (PBMCs) with MT-2 cells and adaption to TALL-1 cells [17].
  • Infection of the human T-cell line MT-2 with EBV recombinants that had a hygromycin resistance gene and subsequent selection with this drug permitted isolation and long-term maintenance of EBV-infected MT-2 clones [18].

Biological context of MT2A

  • When we used antisense MT2A to interdict the effect of MT2A, the inhibition of cell proliferation and induction of apoptosis were significantly enhanced [19].
  • Our data suggest that the physical interaction of EOLA1 and MT2A may have an important role of cell protection in inflammation reaction [20].
  • Using the EOLA1 cDNA as bait, we performed a yeast two-hybrid screening of a human liver cDNA library and identified metallothionein 2A (MT2A) as associated protein [20].
  • Our results are in support of the protective role against oxidative stress ascribed to MTs and provide evidence that MT2A expression may be a beneficial downstream adaptive response in complex I-deficient cells [21].
  • Using human-mouse cell hybrids and hybridization probes derived from cloned and functional human MT1 and MT2 genes, we show that the functional human genes are clustered on human chromosome 16 [22].

Anatomical context of MT2A

  • We conclude that MT2A offers significant protection against the main death-causing consequences of rotenone-induced complex I deficiency in HeLa cells [21].
  • Analysis of RNA from somatic cell hybrids indicated that hybrids that contained human chromosome 16 expressed both human MT1 and MT2 mRNA, and this expression is regulated by both heavy metal ions and glucocorticoid hormones [22].
  • The affinities and the functional activities of these ligands were compared with the human receptors (hMT1 or hMT2) expressed in CHO cells as well [23].
  • When transfected into HTLV-I-infected T-cell lines MT-2 and HUT-102, IL-6 promoter/CAT plasmids were strongly activated without any stimulation [24].
  • In the CNS, MT-I and MT-II are conspicuously absent from neuronal populations, yet abundant in fibrous and protoplasmic astrocytes [25].

Associations of MT2A with chemical compounds

  • Expression of MT2A (MT isoform 2A), but not MT1A or MT1B RNA, was significantly inducible by rotenone (up to 7-fold), t-BHP (t-butyl hydroperoxide; 5-fold) and CdCl2 (50-fold), but not ZnCl2 [21].
  • Molecular pharmacology of the ovine melatonin receptor: comparison with recombinant human MT1 and MT2 receptors [23].
  • 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 [26].
  • Preincubation overnight with 150 microM zinc sulfate or 5 microM cadmium chloride induced a 20- to 30-fold increase of MT2A mRNA; high levels of MT2A mRNA were maintained during the subsequent challenge period with AA, even after the zinc was removed [27].
  • Purified GIF is a 68 amino acid small protein, and its amino acid sequence is 70% identical to that of human metallothionein II with a 1 amino acid insert and a unique 6 amino acid insert in the NH2-terminal and the COOH-terminal portions, respectively [28].

Physical interactions of MT2A


Regulatory relationships of MT2A

  • These cocultured FRTL-5 cells with MT-2 cells expressed IL-6 mRNA and proliferated more actively than those cocultured with CCRF-CEM cells [31].
  • These results suggested that TNF and IFN-beta activate MT-II gene expression by partially distinct mechanisms [32].

Other interactions of MT2A

  • Because metallothioneins are associated with cell proliferation and CR, the PKCmu-MT 2A interaction may contribute to CR and/or AI in PC [29].
  • Metal binding of metallothionein-3 versus metallothionein-2: lower affinity and higher plasticity [30].
  • The goals of this study were to determine the expression of metallothionein isoform 1 and 2 proteins (MT-1 and MT-2) in bladder cancer and then to determine which MT isoform-specific genes promoted the expression of these proteins [3].
  • Expression of MT2- and MT4-MMP was characterized by staining of only a few CD68-negative fibroblasts, and no differences could be found between the lining and sublining [33].
  • In particular, CDC20 and MT2A represent a potential biomarker of human gastric cancer [34].

Analytical, diagnostic and therapeutic context of MT2A


  1. Metallothionein 2A expression is associated with cell proliferation in breast cancer. Jin, R., Chow, V.T., Tan, P.H., Dheen, S.T., Duan, W., Bay, B.H. Carcinogenesis (2002) [Pubmed]
  2. Metallothionein isoform 1 and 2 gene expression in the human prostate: downregulation of MT-1X in advanced prostate cancer. Garrett, S.H., Sens, M.A., Shukla, D., Flores, L., Somji, S., Todd, J.H., Sens, D.A. Prostate (2000) [Pubmed]
  3. Metallothionein isoform 1 and 2 gene expression in the human bladder: evidence for upregulation of MT-1X mRNA in bladder cancer. Somji, S., Sens, M.A., Lamm, D.L., Garrett, S.H., Sens, D.A. Cancer Detect. Prev. (2001) [Pubmed]
  4. Expression of metallothionein II in intestinal metaplasia, dysplasia, and gastric cancer. Ebert, M.P., Günther, T., Hoffmann, J., Yu, J., Miehlke, S., Schulz, H.U., Roessner, A., Korc, M., Malfertheiner, P. Cancer Res. (2000) [Pubmed]
  5. Expression of human metallothionein-II fusion protein in Escherichia coli. Yamazaki, S., Nakanishi, M., Hamamoto, T., Hirata, H., Ebihara, A., Tokue, A., Kagawa, Y. Biochem. Int. (1992) [Pubmed]
  6. Stress gene activity in HepG2 cells after sulfur mustard exposure. Schlager, J.J., Hart, B.W. Journal of applied toxicology : JAT. (2000) [Pubmed]
  7. Species analysis of metallothionein isoforms in human brain cytosols by use of capillary electrophoresis hyphenated to inductively coupled plasma-sector field mass spectrometry. Prange, A., Schaumlöffel, D., Brätter, P., Richarz, A.N., Wolf, C. Fresenius' journal of analytical chemistry. (2001) [Pubmed]
  8. Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Roth, T., Stubbs, C., Walsh, J.K. Sleep. (2005) [Pubmed]
  9. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Hadley, M.E., Dorr, R.T. Peptides (2006) [Pubmed]
  10. Role of hypothalamic interleukin-1beta (IL-1beta) in regulation of energy homeostasis by melanocortins. Wisse, B.E., Ogimoto, K., Schwartz, M.W. Peptides (2006) [Pubmed]
  11. Metallothionein gene cluster is split by chromosome 16 rearrangements in myelomonocytic leukaemia. Le Beau, M.M., Diaz, M.O., Karin, M., Rowley, J.D. Nature (1985) [Pubmed]
  12. alpha-Interferon-induced transcription of HLA and metallothionein genes containing homologous upstream sequences. Friedman, R.L., Stark, G.R. Nature (1985) [Pubmed]
  13. Human metallothionein genes--primary structure of the metallothionein-II gene and a related processed gene. Karin, M., Richards, R.I. Nature (1982) [Pubmed]
  14. A transcription inhibitor, actinomycin D, enhances HIV-1 replication through an interleukin-6-dependent pathway. Imamichi, T., Conrads, T.P., Zhou, M., Liu, Y., Adelsberger, J.W., Veenstra, T.D., Lane, H.C. J. Acquir. Immune Defic. Syndr. (2005) [Pubmed]
  15. The induction of CYP1A1 by oltipraz is mediated through calcium-dependent-calpain. Dale, Y., Eltom, S.E. Toxicol. Lett. (2006) [Pubmed]
  16. Secretion of parathyroid hormone-like activity from human T-cell lymphotropic virus type I-infected lymphocytes. Fukumoto, S., Matsumoto, T., Watanabe, T., Takahashi, H., Miyoshi, I., Ogata, E. Cancer Res. (1989) [Pubmed]
  17. Shorter size of transmembrane glycoprotein of an HIV-1 isolate. Shimizu, H., Morikawa, S., Yamaguchi, K., Tsuchie, H., Hachimori, K., Ushijima, H., Kitamura, T. AIDS (1990) [Pubmed]
  18. Isolation of Epstein-Barr virus-infected clones of the human T-cell line MT-2: use of recombinant viruses with a positive selection marker. Fujiwara, S., Ono, Y. J. Virol. (1995) [Pubmed]
  19. ECRG2, a novel candidate of tumor suppressor gene in the esophageal carcinoma, interacts directly with metallothionein 2A and links to apoptosis. Cui, Y., Wang, J., Zhang, X., Lang, R., Bi, M., Guo, L., Lu, S.H. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  20. Identification and characterization of a novel gene EOLA1 stimulating ECV304 cell proliferation. Liang, Z., Yang, Z. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  21. Metallothionein isoform 2A expression is inducible and protects against ROS-mediated cell death in rotenone-treated HeLa cells. Reinecke, F., Levanets, O., Olivier, Y., Louw, R., Semete, B., Grobler, A., Hidalgo, J., Smeitink, J., Olckers, A., Van der Westhuizen, F.H. Biochem. J. (2006) [Pubmed]
  22. Human metallothionein genes are clustered on chromosome 16. Karin, M., Eddy, R.L., Henry, W.M., Haley, L.L., Byers, M.G., Shows, T.B. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  23. Molecular pharmacology of the ovine melatonin receptor: comparison with recombinant human MT1 and MT2 receptors. Mailliet, F., Audinot, V., Malpaux, B., Bonnaud, A., Delagrange, P., Migaud, M., Barrett, P., Viaud-Massuard, M.C., Lesieur, D., Lefoulon, F., Renard, P., Boutin, J.A. Biochem. Pharmacol. (2004) [Pubmed]
  24. Transcriptional regulation of the human interleukin-6 gene promoter in human T-cell leukemia virus type I-infected T-cell lines: evidence for the involvement of NF-kappa B. Mori, N., Shirakawa, F., Shimizu, H., Murakami, S., Oda, S., Yamamoto, K., Eto, S. Blood (1994) [Pubmed]
  25. The functional significance of brain metallothioneins. Aschner, M. FASEB J. (1996) [Pubmed]
  26. 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]
  27. Metallothionein 2A induction by zinc protects HEPG2 cells against CYP2E1-dependent toxicity. Pérez, M.J., Cederbaum, A.I. Free Radic. Biol. Med. (2003) [Pubmed]
  28. 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]
  29. Metallothionein 2A interacts with the kinase domain of PKCmu in prostate cancer. Rao, P.S., Jaggi, M., Smith, D.J., Hemstreet, G.P., Balaji, K.C. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  30. 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]
  31. Human T cell leukemia virus type I-infected patients with Hashimoto's thyroiditis and Graves' disease. Matsuda, T., Tomita, M., Uchihara, J.N., Okudaira, T., Ohshiro, K., Tomoyose, T., Ikema, T., Masuda, M., Saito, M., Osame, M., Takasu, N., Ohta, T., Mori, N. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  32. Regulation of metallothionein gene expression by TNF-alpha and IFN-beta in human fibroblasts. Sciavolino, P.J., Vilcek, J. Cytokine (1995) [Pubmed]
  33. Differential expression pattern of membrane-type matrix metalloproteinases in rheumatoid arthritis. Pap, T., Shigeyama, Y., Kuchen, S., Fernihough, J.K., Simmen, B., Gay, R.E., Billingham, M., Gay, S. Arthritis Rheum. (2000) [Pubmed]
  34. Identification of gastric cancer-related genes using a cDNA microarray containing novel expressed sequence tags expressed in gastric cancer cells. Kim, J.M., Sohn, H.Y., Yoon, S.Y., Oh, J.H., Yang, J.O., Kim, J.H., Song, K.S., Rho, S.M., Yoo, H.S., Yoo, H.S., Kim, Y.S., Kim, J.G., Kim, N.S. Clin. Cancer Res. (2005) [Pubmed]
  35. Interactions of arsenic with human metallothionein-2. Toyama, M., Yamashita, M., Hirayama, N., Murooka, Y. J. Biochem. (2002) [Pubmed]
  36. Production of the Polyclonal Anti-human Metallothionein 2A Antibody with Recombinant Protein Technology. Marikar, F.M., Sun, Q.M., Hua, Z.C. Acta Biochim. Biophys. Sin. (Shanghai) (2006) [Pubmed]
  37. Construction of cDNA library from NPC tissue and screening of antigenic genes. Shu, J., He, X.J., Li, G.C. Cell. Mol. Immunol. (2006) [Pubmed]
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