Abstract
All metallothioneins (MTs) possess a highly conserved amino acid sequence and present only a few structural changes even when isolated from different animal species. In mammals, a single MT molecule is made up of 61–68 amino acids, depending on the isoform (the MT-1, MT-2, and MT-4 isoforms consist of 61–62 amino acids, whereas the MT-3 isoform comprises 68 amino acids), and the protein sequence is composed of up to 20 cysteine (Cys) residues (Vasak 2005; Vasak and Meloni 2011). Furthermore, in mammals, no aromatic amino acids are found in the MT molecules. Protein sequencing has revealed that the MT molecule is a single polypeptide chain, in which the Cys residues are organized in the sequences Cys-X-Cys, Cys-X-X-Cys, and Cys-Cys, where “X” denotes an amino acid other than Cys (Kojima et al. 1976; Huang and Yoshida 1977). The Cys residues are the metal-binding domains of the MT molecule, in which they are juxtaposed with lysine (Lys) and arginine (Arg) amino acid residues and arranged in two thiol-rich sites designated domains α and β (Fig. 2.1). The two metal-binding domains are separated by a non-cysteine-containing sequence often designated as the spacer or linker (Zangger et al. 2001; Babula et al. 2012). The α-domain consists of amino acids 31–68 and is located on the C-terminal edge, whereas the N-terminal β-domain contains amino acids 1–30 (Zangger et al. 2001; Dziegiel 2004). It has been demonstrated that the α-domain is capable of binding up to four, and the β-domain up to three, bivalent metal ions such as zinc, cadmium, mercury, or lead (Coyle et al. 2002b; Duncan et al. 2006). The part of the protein with no bound metal ions is termed apo-metallothionein (apo-MT) or thionein (Coyle et al. 2002b). Metallothioneins are also capable of reacting with up to 12 univalent metal ions (Palmiter 1998; Coyle et al. 2002b). Zinc ions, which naturally occur in the organism, are regarded as the main binding partner of apo-MT. However, other nonessential metal ions occurring pathologically in the organism—such as lead, copper, cadmium, mercury, platinum, chromate, bismuth, and silver—often possess higher affinity to the apo-MT-binding sites (Nordberg and Nordberg 2000; Ngu and Stillman 2009; Ngu et al. 2010b; Gumulec et al. 2011; Babula et al. 2012). So far, only iron ions (Fe2+) have been identified to possess lower affinity to the metal-binding sites of the apo-MT domains (Foster and Robinson 2011). Interestingly, only a small proportion of MT molecules was found bound to zinc ions in various organisms. In rat tissues, apo-MT has been shown to constitute up to 54 % of the total amount of MT, whereas higher apo-MT levels were detected in rat cancer cells (Yang et al. 2001). Recent studies have also identified small amounts of sulfide ligands bound to recombinant MT-1 and MT-4 proteins overexpressed in Escherichia coli (Capdevila et al. 2005; Tio et al. 2006). Nevertheless, studies analyzing MT proteins in the cytoplasm of mammalian cells have failed to detect sulfide ligands bound to their molecules (Mounicou et al. 2010).
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References
Abdel-Mageed AB, Agrawal KC (1998) Activation of nuclear factor kappaB: potential role in metallothionein-mediated mitogenic response. Cancer Res 58(11):2335–2338
Abel J, de Ruiter N (1989) Inhibition of hydroxyl-radical-generated DNA degradation by metallothionein. Toxicol Lett 47(2):191–196
Adam V, Petrlova J, Wang J, Eckschlager T, Trnkova L, Kizek R (2010) Zeptomole electrochemical detection of metallothioneins. PLoS One 5(7), e11441
Ala S, Shokrzadeh M, Golpour M, Salehifar E, Alami M, Ahmadi A (2013) Zinc and copper levels in Iranian patients with psoriasis: a case control study. Biol Trace Elem Res 153(1–3):22–27
Andrews GK (2000) Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem Pharmacol 59(1):95–104
Andrews PA, Murphy MP, Howell SB (1987) Metallothionein-mediated cisplatin resistance in human ovarian carcinoma cells. Cancer Chemother Pharmacol 19(2):149–154
Apostolova MD, Ivanova IA, Cherian MG (1999) Metallothionein and apoptosis during differentiation of myoblasts to myotubes: protection against free radical toxicity. Toxicol Appl Pharmacol 159(3):175–184
Apostolova MD, Ivanova IA, Cherian MG (2000) Signal transduction pathways, and nuclear translocation of zinc and metallothionein during differentiation of myoblasts. Biochem Cell Biol 78(1):27–37
Apostolova MD, Chen S, Chakrabarti S, Cherian MG (2001) High-glucose-induced metallothionein expression in endothelial cells: an endothelin-mediated mechanism. Am J Physiol Cell Physiol 281(3):C899–907
Aschner M, Syversen T, Souza DO, Rocha JB (2006) Metallothioneins: mercury species-specific induction and their potential role in attenuating neurotoxicity. Exp Biol Med (Maywood) 231(9):1468–1473
Babula P, Masarik M, Adam V, Eckschlager T, Stiborova M, Trnkova L, Skutkova H, Provaznik I, Hubalek J, Kizek R (2012) Mammalian metallothioneins: properties and functions. Metallomics 4(8):739–750
Baird SK, Kurz T, Brunk UT (2006) Metallothionein protects against oxidative stress-induced lysosomal destabilization. Biochem J 394(Pt 1):275–283
Banerjee D, Onosaka S, Cherian MG (1982) Immunohistochemical localization of metallothionein in cell nucleus and cytoplasm of rat liver and kidney. Toxicology 24(2):95–105
Bedrnicek J, Vicha A, Jarosova M, Holzerova M, Cinatl J Jr, Michaelis M, Cinatl J, Eckschlager T (2005) Characterization of drug-resistant neuroblastoma cell lines by comparative genomic hybridization. Neoplasma 52(5):415–419
Bi Y, Palmiter RD, Wood KM, Ma Q (2004) Induction of metallothionein I by phenolic antioxidants requires metal-activated transcription factor 1 (MTF-1) and zinc. Biochem J 380(Pt 3):695–703
Borthiry GR, Antholine WE, Kalyanaraman B, Myers JM, Myers CR (2007) Reduction of hexavalent chromium by human cytochrome b5: generation of hydroxyl radical and superoxide. Free Radic Biol Med 42(6):738–755, discussion 735-737
Borthiry GR, Antholine WE, Myers JM, Myers CR (2008) Addition of DNA to Cr(VI) and cytochrome b5 containing proteoliposomes leads to generation of DNA strand breaks and Cr(III) complexes. Chem Biodivers 5(8):1545–1557
Brandao R, Santos FW, Farina M, Zeni G, Bohrer D, Rocha JB, Nogueira CW (2006) Antioxidants and metallothionein levels in mercury-treated mice. Cell Biol Toxicol 22(6):429–438
Butcher HL, Kennette WA, Collins O, Zalups RK, Koropatnick J (2004) Metallothionein mediates the level and activity of nuclear factor kappa B in murine fibroblasts. J Pharmacol Exp Ther 310(2):589–598
Cai L, Satoh M, Tohyama C, Cherian MG (1999) Metallothionein in radiation exposure: its induction and protective role. Toxicology 132(2–3):85–98
Cai B, Zheng Q, Huang ZX (2005) The properties of the metal-thiolate clusters in recombinant mouse metallothionein-4. Protein J 24(6):327–336
Campagne MV, Thibodeaux H, van Bruggen N, Cairns B, Lowe DG (2000) Increased binding activity at an antioxidant-responsive element in the metallothionein-1 promoter and rapid induction of metallothionein-1 and -2 in response to cerebral ischemia and reperfusion. J Neurosci 20(14):5200–5207
Cano-Gauci DF, Sarkar B (1996) Reversible zinc exchange between metallothionein and the estrogen receptor zinc finger. FEBS Lett 386(1):1–4
Capdevila M, Domenech J, Pagani A, Tio L, Villarreal L, Atrian S (2005) Zn- and Cd-metallothionein recombinant species from the most diverse phyla may contain sulfide (S2-) ligands. Angew Chem Int Ed Engl 44(29):4618–4622
Chan HM, Satoh M, Zalups RK, Cherian MG (1992) Exogenous metallothionein and renal toxicity of cadmium and mercury in rats. Toxicology 76(1):15–26
Chapman GA, Kay J, Kille P (1999) Structural and functional analysis of the rat metallothionein III genomic locus. Biochim Biophys Acta 1445(3):321–329
Chasapis CT, Loutsidou AC, Spiliopoulou CA, Stefanidou ME (2012) Zinc and human health: an update. Arch Toxicol 86(4):521–534
Chen Y, Irie Y, Keung WM, Maret W (2002) S-nitrosothiols react preferentially with zinc thiolate clusters of metallothionein III through transnitrosation. Biochemistry 41(26):8360–8367
Chen WY, John JA, Lin CH, Lin HF, Wu SC, Chang CY (2004) Expression of metallothionein gene during embryonic and early larval development in zebrafish. Aquat Toxicol 69(3):215–227
Cherian MG, Apostolova MD (2000) Nuclear localization of metallothionein during cell proliferation and differentiation. Cell Mol Biol (Noisy-le-grand) 46(2):347–356
Cherian MG, Kang YJ (2006) Metallothionein and liver cell regeneration. Exp Biol Med (Maywood) 231(2):138–144
Cherian MG, Jayasurya A, Bay BH (2003) Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat Res 533(1–2):201–209
Chiaverini N, De Ley M (2010) Protective effect of metallothionein on oxidative stress-induced DNA damage. Free Radic Res 44(6):605–613
Choi CH, Cha YJ, An CS, Kim KJ, Kim KC, Moon SP, Lee ZH, Min YD (2004) Molecular mechanisms of heptaplatin effective against cisplatin-resistant cancer cell lines: less involvement of metallothionein. Cancer Cell Int 4(1):6
Chubatsu LS, Gennari M, Meneghini R (1992) Glutathione is the antioxidant responsible for resistance to oxidative stress in V79 Chinese hamster fibroblasts rendered resistant to cadmium. Chem Biol Interact 82(1):99–110
Chun JH, Kim HK, Kim E, Kim IH, Kim JH, Chang HJ, Choi IJ, Lim HS, Kim IJ, Kang HC, Park JH, Bae JM, Park JG (2004) Increased expression of metallothionein is associated with irinotecan resistance in gastric cancer. Cancer Res 64(14):4703–4706
Conrad CC, Grabowski DT, Walter CA, Sabia M, Richardson A (2000) Using MT(-/-) mice to study metallothionein and oxidative stress. Free Radic Biol Med 28(3):447–462
Coyle P, Philcox JC, Carey LC, Rofe AM (2002b) Metallothionein: the multipurpose protein. Cell Mol Life Sci 59(4):627–647
Davis SR, Cousins RJ (2000) Metallothionein expression in animals: a physiological perspective on function. J Nutr 130(5):1085–1088
Davis SR, Samuelson DA, Cousins RJ (2001) Metallothionein expression protects against carbon tetrachloride-induced hepatotoxicity, but overexpression and dietary zinc supplementation provide no further protection in metallothionein transgenic and knockout mice. J Nutr 131(2):215–222
Deng D, El-Rifai W, Ji J, Zhu B, Trampont P, Li J, Smith MF, Powel SM (2003a) Hypermethylation of metallothionein-3 CpG island in gastric carcinoma. Carcinogenesis 24(1):25–29
Deng D, El-Rifai W, Ji J, Zhu B, Trampont P, Li J, Smith MF, Powel SM (2003b) Hypermethylation of metallothionein-3 CpG island in gastric carcinoma. Carcinogenesis 24(1):25–29
Ding ZC, Ni FY, Huang ZX (2010) Neuronal growth-inhibitory factor (metallothionein-3): structure-function relationships. FEBS J 277(14):2912–2920
Duncan KE, Ngu TT, Chan J, Salgado MT, Merrifield ME, Stillman MJ (2006) Peptide folding, metal-binding mechanisms, and binding site structures in metallothioneins. Exp Biol Med (Maywood) 231(9):1488–1499
Dziegiel P (2004) Expression of metallothioneins in tumor cells. Pol J Pathol 55(1):3–12
Dziegiel P, Salwa-Zurawska W, Zurawski J, Wojnar A, Zabel M (2005) Prognostic significance of augmented metallothionein (MT) expression correlated with Ki-67 antigen expression in selected soft tissue sarcomas. Histol Histopathol 20(1):83–89
Eibl JK, Abdallah Z, Ross GM (2010) Zinc-metallothionein: a potential mediator of antioxidant defence mechanisms in response to dopamine-induced stress. Can J Physiol Pharmacol 88(3):305–312
Faller P (2010) Neuronal growth-inhibitory factor (metallothionein-3): reactivity and structure of metal-thiolate clusters. FEBS J 277(14):2921–2930
Fan LZ, Cherian MG (2002) Potential role of p53 on metallothionein induction in human epithelial breast cancer cells. Br J Cancer 87(9):1019–1026
Formigari A, Irato P, Santon A (2007) Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: biochemical and cytochemical aspects. Comp Biochem Physiol C Toxicol Pharmacol 146(4):443–459
Formigari A, Gregianin E, Irato P (2013) The effect of zinc and the role of p53 in copper-induced cellular stress responses. J Appl Toxicol 33(7):527–536
Foster AW, Robinson NJ (2011) Promiscuity and preferences of metallothioneins: the cell rules. BMC Biol 9:25
Garrett SH, Phillips V, Somji S, Sens MA, Dutta R, Park S, Kim D, Sens DA (2002) Transient induction of metallothionein isoform 3 (MT-3), c-fos, c-jun and c-myc in human proximal tubule cells exposed to cadmium. Toxicol Lett 126(1):69–80
Gauthier MA, Eibl JK, Crispo JA, Ross GM (2008) Covalent arylation of metallothionein by oxidized dopamine products: a possible mechanism for zinc-mediated enhancement of dopaminergic neuron survival. Neurotox Res 14(4):317–328
Ghoshal K, Jacob ST (2001) Regulation of metallothionein gene expression. Prog Nucleic Acid Res Mol Biol 66:357–384
Ghoshal K, Wang Y, Sheridan JF, Jacob ST (1998) Metallothionein induction in response to restraint stress. Transcriptional control, adaptation to stress, and role of glucocorticoid. J Biol Chem 273(43):27904–27910
Ghoshal K, Majumder S, Li Z, Bray TM, Jacob ST (1999) Transcriptional induction of metallothionein-I and -II genes in the livers of Cu, Zn-superoxide dismutase knockout mice. Biochem Biophys Res Commun 264(3):735–742
Gilmore TD (2006) Introduction to NF-kappaB: players, pathways, perspectives. Oncogene 25(51):6680–6684
Goering PL, Klaassen CD (1983) Altered subcellular distribution of cadmium following cadmium pretreatment: possible mechanism of tolerance to cadmium-induced lethality. Toxicol Appl Pharmacol 70(2):195–203
Goering PL, Klaassen CD (1984) Resistance to cadmium-induced hepatotoxicity in immature rats. Toxicol Appl Pharmacol 74(3):321–329
Gomulkiewicz A, Podhorska-Okolow M, Szulc R, Smorag Z, Wojnar A, Zabel M, Dziegiel P (2010) Correlation between metallothionein (MT) expression and selected prognostic factors in ductal breast cancers. Folia Histochem Cytobiol 48(2):242–248
Groten JP, Koeman JH, van Nesselrooij JH, Luten JB, Fentener van Vlissingen JM, Stenhuis WS, van Bladeren PJ (1994) Comparison of renal toxicity after long-term oral administration of cadmium chloride and cadmium-metallothionein in rats. Fundam Appl Toxicol 23(4):544–552
Gumulec J, Masarik M, Krizkova S, Adam V, Hubalek J, Hrabeta J, Eckschlager T, Stiborova M, Kizek R (2011) Insight to physiology and pathology of zinc(II) ions and their actions in breast and prostate carcinoma. Curr Med Chem 18(33):5041–5051
Gunes C, Heuchel R, Georgiev O, Muller KH, Lichtlen P, Bluthmann H, Marino S, Aguzzi A, Schaffner W (1998) Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1. EMBO J 17(10):2846–2854
Habeebu SS, Liu J, Liu Y, Klaassen CD (2000a) Metallothionein-null mice are more sensitive than wild-type mice to liver injury induced by repeated exposure to cadmium. Toxicol Sci 55(1):223–232
Habeebu SS, Liu J, Liu Y, Klaassen CD (2000b) Metallothionein-null mice are more susceptible than wild-type mice to chronic CdCl(2)-induced bone injury. Toxicol Sci 56(1):211–219
Hamza-Chaffai A, Amiard JC, Cosson RP (1999) Relationship between metallothioneins and metals in a natural population of the clam Ruditapes decussatus from Sfax coast: a non-linear model using Box-Cox transformation. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 123(2):153–163
Han YC, Zheng ZL, Zuo ZH, Yu YP, Chen R, Tseng GC, Nelson JB, Luo JH (2013) Metallothionein 1 h tumour suppressor activity in prostate cancer is mediated by euchromatin methyltransferase 1. J Pathol 230(2):184–193
Haq F, Mahoney M, Koropatnick J (2003) Signaling events for metallothionein induction. Mutat Res 533(1–2):211–226
Hart BA, Voss GW, Willean CL (1989) Pulmonary tolerance to cadmium following cadmium aerosol pretreatment. Toxicol Appl Pharmacol 101(3):447–460
Hart BA, Gong Q, Eneman JD, Durieux-Lu CC (1995) In vivo expression of metallothionein in rat alveolar macrophages and type II epithelial cells following repeated cadmium aerosol exposures. Toxicol Appl Pharmacol 133(1):82–90
Hart BA, Potts RJ, Watkin RD (2001) Cadmium adaptation in the lung - a double-edged sword? Toxicology 160(1–3):65–70
Hatcher EL, Alexander JM, Kang YJ (1997) Decreased sensitivity to adriamycin in cadmium-resistant human lung carcinoma A549 cells. Biochem Pharmacol 53(5):747–754
Hayes RA, Regondi S, Winter MJ, Butler PJ, Agradi E, Taylor EW, Kevin Chipman J (2004) Cloning of a chub metallothionein cDNA and development of competitive RT-PCR of chub metallothionein mRNA as a potential biomarker of heavy metal exposure. Mar Environ Res 58(2–5):665–669
Hernandez J, Carrasco J, Belloso E, Giralt M, Bluethmann H, Kee Lee D, Andrews GK, Hidalgo J (2000) Metallothionein induction by restraint stress: role of glucocorticoids and IL-6. Cytokine 12(6):791–796
Heuchel R, Radtke F, Georgiev O, Stark G, Aguet M, Schaffner W (1994) The transcription factor MTF-1 is essential for basal and heavy metal-induced metallothionein gene expression. EMBO J 13(12):2870–2875
Higashimoto M, Isoyama N, Ishibashi S, Inoue M, Takiguchi M, Suzuki S, Ohnishi Y, Sato M (2009) Tissue-dependent preventive effect of metallothionein against DNA damage in dyslipidemic mice under repeated stresses of fasting or restraint. Life Sci 84(17–18):569–575
Hishikawa Y, Abe S, Kinugasa S, Yoshimura H, Monden N, Igarashi M, Tachibana M, Nagasue N (1997) Overexpression of metallothionein correlates with chemoresistance to cisplatin and prognosis in esophageal cancer. Oncology 54(4):342–347
Hoogenraad TU (2006) Paradigm shift in treatment of Wilson's disease: zinc therapy now treatment of choice. Brain Dev 28(3):141–146
Huang IY, Yoshida A (1977) Mouse liver metallothioneins. Complete amino acid sequence of metallothionein-I. J Biol Chem 252(22):8217–8221
Huang M, Shaw IC, Petering DH (2004) Interprotein metal exchange between transcription factor IIIa and apo-metallothionein. J Inorg Biochem 98(4):639–648
Hwang TL, Chen HY, Changchien TT, Wang CC, Wu CM (2013) The cytotoxicity of mercury chloride to the keratinocytes is associated with metallothionein expression. Biomed Rep 1(3):379–382
Iwata M, Takebayashi T, Ohta H, Alcalde RE, Itano Y, Matsumura T (1999) Zinc accumulation and metallothionein gene expression in the proliferating epidermis during wound healing in mouse skin. Histochem Cell Biol 112(4):283–290
Jacob ST, Ghoshal K, Sheridan JF (1999) Induction of metallothionein by stress and its molecular mechanisms. Gene Expr 7(4–6):301–310
Jia G, Gu YQ, Chen KT, Lu YY, Yan L, Wang JL, Su YP, Wu JC (2004a) Protective role of metallothionein (I/II) against pathological damage and apoptosis induced by dimethylarsinic acid. World J Gastroenterol 10(1):91–95
Jin R, Chow VT, Tan PH, Dheen ST, Duan W, Bay BH (2002) Metallothionein 2A expression is associated with cell proliferation in breast cancer. Carcinogenesis 23(1):81–86
Karasawa M, Nishimura N, Nishimura H, Tohyama C, Hashiba H, Kuroki T (1991) Localization of metallothionein in hair follicles of normal skin and the basal cell layer of hyperplastic epidermis: possible association with cell proliferation. J Invest Dermatol 97(1):97–100
Kenaga C, Cherian MG, Cox C, Oberdorster G (1996) Metallothionein induction and pulmonary responses to inhaled cadmium chloride in rats and mice. Fundam Appl Toxicol 30(2):204–212
Khan KH, Blanco-Codesido M, Molife LR (2014) Cancer therapeutics: Targeting the apoptotic pathway. Crit Rev Oncol Hematol 90(3):200–219
Kim CH, Kim JH, Lee J, Ahn YS (2003) Zinc-induced NF-kappaB inhibition can be modulated by changes in the intracellular metallothionein level. Toxicol Appl Pharmacol 190(2):189–196
Klein D, Lichtmannegger J, Heinzmann U, Muller-Hocker J, Michaelsen S, Summer KH (1998) Association of copper to metallothionein in hepatic lysosomes of Long-Evans cinnamon (LEC) rats during the development of hepatitis. Eur J Clin Invest 28(4):302–310
Koizumi S, Suzuki K, Ogra Y, Yamada H, Otsuka F (1999) Transcriptional activity and regulatory protein binding of metal-responsive elements of the human metallothionein-IIA gene. Eur J Biochem 259(3):635–642
Kojima Y, Berger C, Vallee BL, Kagi JH (1976) Amino-acid sequence of equine renal metallothionein-1B. Proc Natl Acad Sci USA 73(10):3413–3417
Kojima I, Tanaka T, Inagi R, Nishi H, Aburatani H, Kato H, Miyata T, Fujita T, Nangaku M (2009) Metallothionein is upregulated by hypoxia and stabilizes hypoxia-inducible factor in the kidney. Kidney Int 75(3):268–277
Kondo Y, Rusnak JM, Hoyt DG, Settineri CE, Pitt BR, Lazo JS (1997) Enhanced apoptosis in metallothionein null cells. Mol Pharmacol 52(2):195–201
Krepkiy D, Antholine WE, Petering DH (2003) Properties of the reaction of chromate with metallothionein. Chem Res Toxicol 16(6):750–756
Kreppel H, Bauman JW, Liu J, McKim JM Jr, Klaassen CD (1993) Induction of metallothionein by arsenicals in mice. Fundam Appl Toxicol 20(2):184–189
Krizkova S, Adam V, Kizek R (2009a) Study of metallothionein oxidation by using of chip CE. Electrophoresis 30(23):4029–4033
Krizkova S, Fabrik I, Adam V, Hrabeta J, Eckschlager T, Kizek R (2009b) Metallothionein--a promising tool for cancer diagnostics. Bratisl Lek Listy 110(2):93–97
Krizkova S, Masarik M, Majzlik P, Kukacka J, Kruseova J, Adam V, Prusa R, Eckschlager T, Stiborova M, Kizek R (2010) Serum metallothionein in newly diagnosed patients with childhood solid tumours. Acta Biochim Pol 57(4):561–566
Krizkova S, Ryvolova M, Hrabeta J, Adam V, Stiborova M, Eckschlager T, Kizek R (2012) Metallothioneins and zinc in cancer diagnosis and therapy. Drug Metab Rev 44(4):287–301
Kruseova J, Hynek D, Adam V, Kizek R, Prusa R, Hrabeta J, Eckschlager T (2013) Serum metallothioneins in childhood tumours-a potential prognostic marker. Int J Mol Sci 14(6):12170–12185
Kumar P, Lal NR, Mondal AK, Mondal A, Gharami RC, Maiti A (2012) Zinc and skin: a brief summary. Dermatol Online J 18(3):1
Langmade SJ, Ravindra R, Daniels PJ, Andrews GK (2000) The transcription factor MTF-1 mediates metal regulation of the mouse ZnT1 gene. J Biol Chem 275(44):34803–34809
Lee SJ, Koh JY (2010) Roles of zinc and metallothionein-3 in oxidative stress-induced lysosomal dysfunction, cell death, and autophagy in neurons and astrocytes. Mol Brain 3(1):30
Lee SJ, Park MH, Kim HJ, Koh JY (2010) Metallothionein-3 regulates lysosomal function in cultured astrocytes under both normal and oxidative conditions. Glia 58(10):1186–1196
Levadoux-Martin M, Hesketh JE, Beattie JH, Wallace HM (2001) Influence of metallothionein-1 localization on its function. Biochem J 355(Pt 2):473–479
Liang L, Fu K, Lee DK, Sobieski RJ, Dalton T, Andrews GK (1996) Activation of the complete mouse metallothionein gene locus in the maternal deciduum. Mol Reprod Dev 43(1):25–37
Lichtlen P, Schaffner W (2001) The "metal transcription factor" MTF-1: biological facts and medical implications. Swiss Med Wkly 131(45–46):647–652
Lim D, Jocelyn KM, Yip GW, Bay BH (2009) Silencing the Metallothionein-2A gene inhibits cell cycle progression from G1- to S-phase involving ATM and cdc25A signaling in breast cancer cells. Cancer Lett 276(1):109–117
Liu J, Liu Y, Klaassen CD (1994) Nephrotoxicity of CdCl2 and Cd-metallothionein in cultured rat kidney proximal tubules and LLC-PK1 cells. Toxicol Appl Pharmacol 128(2):264–270
Liu Y, Liu J, Iszard MB, Andrews GK, Palmiter RD, Klaassen CD (1995) Transgenic mice that overexpress metallothionein-I are protected from cadmium lethality and hepatotoxicity. Toxicol Appl Pharmacol 135(2):222–228
Liu J, Liu Y, Michalska AE, Choo KH, Klaassen CD (1996) Metallothionein plays less of a protective role in cadmium-metallothionein-induced nephrotoxicity than in cadmium chloride-induced hepatotoxicity. J Pharmacol Exp Ther 276(3):1216–1223
Liu J, Liu Y, Habeebu SS, Klaassen CD (1998) Susceptibility of MT-null mice to chronic CdCl2-induced nephrotoxicity indicates that renal injury is not mediated by the CdMT complex. Toxicol Sci 46(1):197–203
Liu J, Liu Y, Goyer RA, Achanzar W, Waalkes MP (2000a) Metallothionein-I/II null mice are more sensitive than wild-type mice to the hepatotoxic and nephrotoxic effects of chronic oral or injected inorganic arsenicals. Toxicol Sci 55(2):460–467
Liu J, Liu Y, Habeebu SM, Waalkes MP, Klaassen CD (2000b) Chronic combined exposure to cadmium and arsenic exacerbates nephrotoxicity, particularly in metallothionein-I/II null mice. Toxicology 147(3):157–166
Liu ZM, Chen GG, Shum CK, Vlantis AC, Cherian MG, Koropatnick J, van Hasselt CA (2007) Induction of functional MT1 and MT2 isoforms by calcium in anaplastic thyroid carcinoma cells. FEBS Lett 581(13):2465–2472
Liu ZM, Hasselt CA, Song FZ, Vlantis AC, Cherian MG, Koropatnick J, Chen GG (2009) Expression of functional metallothionein isoforms in papillary thyroid cancer. Mol Cell Endocrinol 302(1):92–98
MacDonald RS (2000) The role of zinc in growth and cell proliferation. J Nutr 130(5S Suppl):1500S–1508S
Mao J, Yu H, Wang C, Sun L, Jiang W, Zhang P, Xiao Q, Han D, Saiyin H, Zhu J, Chen T, Roberts LR, Huang H, Yu L (2012) Metallothionein MT1M is a tumor suppressor of human hepatocellular carcinomas. Carcinogenesis 33(12):2568–2577
Maret W, Vallee BL (1998) Thiolate ligands in metallothionein confer redox activity on zinc clusters. Proc Natl Acad Sci USA 95(7):3478–3482
Maret W, Larsen KS, Vallee BL (1997) Coordination dynamics of biological zinc “clusters” in metallothioneins and in the DNA-binding domain of the transcription factor Gal4. Proc Natl Acad Sci USA 94(6):2233–2237
McGee HM, Woods GM, Bennett B, Chung RS (2010) The two faces of metallothionein in carcinogenesis: photoprotection against UVR-induced cancer and promotion of tumour survival. Photochem Photobiol Sci 9(4):586–596
Meloni G, Zovo K, Kazantseva J, Palumaa P, Vasak M (2006) Organization and assembly of metal-thiolate clusters in epithelium-specific metallothionein-4. J Biol Chem 281(21):14588–14595
Meplan C, Verhaegh G, Richard MJ, Hainaut P (1999) Metal ions as regulators of the conformation and function of the tumour suppressor protein p53: implications for carcinogenesis. Proc Nutr Soc 58(3):565–571
Meplan C, Richard MJ, Hainaut P (2000) Redox signalling and transition metals in the control of the p53 pathway. Biochem Pharmacol 59(1):25–33
Mididoddi S, McGuirt JP, Sens MA, Todd JH, Sens DA (1996) Isoform-specific expression of metallothionein mRNA in the developing and adult human kidney. Toxicol Lett 85(1):17–27
Milnerowicz H, Jablonowska M, Bizon A (2009) Change of zinc, copper, and metallothionein concentrations and the copper-zinc superoxide dismutase activity in patients with pancreatitis. Pancreas 38(6):681–688
Mita M, Satoh M, Shimada A, Okajima M, Azuma S, Suzuki JS, Sakabe K, Hara S, Himeno S (2008) Metallothionein is a crucial protective factor against Helicobacter pylori-induced gastric erosive lesions in a mouse model. Am J Physiol Gastrointest Liver Physiol 294(4):G877–884
Monnet-Tschudi F, Zurich MG, Boschat C, Corbaz A, Honegger P (2006) Involvement of environmental mercury and lead in the etiology of neurodegenerative diseases. Rev Environ Health 21(2):105–117
Mounicou S, Ouerdane L, L'Azou B, Passagne I, Ohayon-Courtes C, Szpunar J, Lobinski R (2010) Identification of metallothionein subisoforms in HPLC using accurate mass and online sequencing by electrospray hybrid linear ion trap-orbital ion trap mass spectrometry. Anal Chem 82(16):6947–6957
Mukhopadhyay D, Mitra A, Nandi P, Varghese AC, Murmu N, Chowdhury R, Chaudhuri K, Bhattacharyya AK (2009) Expression of metallothionein-1 (MT-1) mRNA in the rat testes and liver after cadmium injection. Syst Biol Reprod Med 55(5–6):188–192
Murata M, Gong P, Suzuki K, Koizumi S (1999) Differential metal response and regulation of human heavy metal-inducible genes. J Cell Physiol 180(1):105–113
Murphy BJ, Kimura T, Sato BG, Shi Y, Andrews GK (2008) Metallothionein induction by hypoxia involves cooperative interactions between metal-responsive transcription factor-1 and hypoxia-inducible transcription factor-1alpha. Mol Cancer Res 6(3):483–490
Nagel WW, Vallee BL (1995) Cell cycle regulation of metallothionein in human colonic cancer cells. Proc Natl Acad Sci USA 92(2):579–583
Nartey NO, Frei JV, Cherian MG (1987b) Hepatic copper and metallothionein distribution in Wilson's disease (hepatolenticular degeneration). Lab Invest 57(4):397–401
Ngu TT, Stillman MJ (2006) Arsenic binding to human metallothionein. J Am Chem Soc 128(38):12473–12483
Ngu TT, Stillman MJ (2009) Metalation of metallothioneins. IUBMB Life 61(4):438–446
Ngu TT, Dryden MD, Stillman MJ (2010a) Arsenic transfer between metallothionein proteins at physiological pH. Biochem Biophys Res Commun 401(1):69–74
Ngu TT, Krecisz S, Stillman MJ (2010b) Bismuth binding studies to the human metallothionein using electrospray mass spectrometry. Biochem Biophys Res Commun 396(2):206–212
Nguyen T, Sherratt PJ, Pickett CB (2003) Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 43:233–260
Nielsen AE, Bohr A, Penkowa M (2007) The Balance between Life and Death of Cells: Roles of Metallothioneins. Biomark Insights 7(1):99–111
Nielson KB, Atkin CL, Winge DR (1985) Distinct metal-binding configurations in metallothionein. J Biol Chem 260(9):5342–5350
Nordberg M, Nordberg GF (2000) Toxicological aspects of metallothionein. Cell Mol Biol (Noisy-le-grand) 46(2):451–463
Nordberg GF, Goyer R, Nordberg M (1975) Comparative toxicity of cadmium-metallothionein and cadmium chloride on mouse kidney. Arch Pathol 99(4):192–197
Nordberg GF, Garvey JS, Chang CC (1982) Metallothionein in plasma and urine of cadmium workers. Environ Res 28(1):179–182
Nzengue Y, Lefebvre E, Cadet J, Favier A, Rachidi W, Steiman R, Guiraud P (2009) Metallothionein expression in HaCaT and C6 cell lines exposed to cadmium. J Trace Elem Med Biol 23(4):314–323
Oda N, Sogawa CA, Sogawa N, Onodera K, Furuta H, Yamamoto T (2001) Metallothionein expression and localization in rat bone tissue after cadmium injection. Toxicol Lett 123(2–3):143–150
Ogra Y, Suzuki KT (2000) Nuclear trafficking of metallothionein: possible mechanisms and current knowledge. Cell Mol Biol (Noisy-le-grand) 46(2):357–365
Olesen C, Moller M, Byskov AG (2004) Tesmin transcription is regulated differently during male and female meiosis. Mol Reprod Dev 67(1):116–126
Ostrakhovitch EA, Cherian MG (2004) Differential regulation of signal transduction pathways in wild type and mutated p53 breast cancer epithelial cells by copper and zinc. Arch Biochem Biophys 423(2):351–361
Ostrakhovitch EA, Olsson PE, Jiang S, Cherian MG (2006) Interaction of metallothionein with tumor suppressor p53 protein. FEBS Lett 580(5):1235–1238
Ostrakhovitch EA, Olsson PE, von Hofsten J, Cherian MG (2007) P53 mediated regulation of metallothionein transcription in breast cancer cells. J Cell Biochem 102(6):1571–1583
Otsuka F, Okugaito I, Ohsawa M, Iwamatsu A, Suzuki K, Koizumi S (2000) Novel responses of ZRF, a variant of human MTF-1, to in vivo treatment with heavy metals. Biochim Biophys Acta 1492(2–3):330–340
Palacios O, Atrian S, Capdevila M (2011) Zn- and Cu-thioneins: a functional classification for metallothioneins? J Biol Inorg Chem 16(7):991–1009
Palecek E, Brazdova M, Cernocka H, Vlk D, Brazda V, Vojtesek B (1999) Effect of transition metals on binding of p53 protein to supercoiled DNA and to consensus sequence in DNA fragments. Oncogene 18(24):3617–3625
Palmiter RD (1998) The elusive function of metallothioneins. Proc Natl Acad Sci USA 95(15):8428–8430
Palmiter RD, Findley SD, Whitmore TE, Durnam DM (1992) MT-III, a brain-specific member of the metallothionein gene family. Proc Natl Acad Sci USA 89(14):6333–6337
Palumaa P, Njunkova O, Pokras L, Eriste E, Jornvall H, Sillard R (2002) Evidence for non-isostructural replacement of Zn(2+) with Cd(2+) in the beta-domain of brain-specific metallothionein-3. FEBS Lett 527(1–3):76–80
Palumaa P, Eriste E, Kruusel K, Kangur L, Jornvall H, Sillard R (2003) Metal binding to brain-specific metallothionein-3 studied by electrospray ionization mass spectrometry. Cell Mol Biol (Noisy-le-grand) 49(5):763–768
Palumaa P, Tammiste I, Kruusel K, Kangur L, Jornvall H, Sillard R (2005) Metal binding of metallothionein-3 versus metallothionein-2: lower affinity and higher plasticity. Biochim Biophys Acta 1747(2):205–211
Papouli E, Defais M, Larminat F (2002) Overexpression of metallothionein-II sensitizes rodent cells to apoptosis induced by DNA cross-linking agent through inhibition of NF-kappa B activation. J Biol Chem 277(7):4764–4769
Park YH, Lee YM, Kim DS, Park J, Suk K, Kim JK, Han HS (2013) Hypothermia enhances induction of protective protein metallothionein under ischemia. J Neuroinflammation 10:21
Pearson CA, Lamar PC, Prozialeck WC (2003) Effects of cadmium on E-cadherin and VE-cadherin in mouse lung. Life Sci 72(11):1303–1320
Pedersen MO, Larsen A, Stoltenberg M, Penkowa M (2009) The role of metallothionein in oncogenesis and cancer prognosis. Prog Histochem Cytochem 44(1):29–64
Peixoto NC, Serafim MA, Flores EM, Bebianno MJ, Pereira ME (2007) Metallothionein, zinc, and mercury levels in tissues of young rats exposed to zinc and subsequently to mercury. Life Sci 81(16):1264–1271
Penkowa M, Tio L, Giralt M, Quintana A, Molinero A, Atrian S, Vasak M, Hidalgo J (2006) Specificity and divergence in the neurobiologic effects of different metallothioneins after brain injury. J Neurosci Res 83(6):974–984
Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 8(1):49–62
Person RJ, Tokar EJ, Xu Y, Orihuela R, Ngalame NN, Waalkes MP (2013) Chronic cadmium exposure in vitro induces cancer cell characteristics in human lung cells. Toxicol Appl Pharmacol 273(2):281–288
Petering DH, Huang M, Moteki S, Shaw CF 3rd (2000) Cadmium and lead interactions with transcription factor IIIA from Xenopus laevis: a model for zinc finger protein reactions with toxic metal ions and metallothionein. Mar Environ Res 50(1–5):89–92
Podhorska-Okolow M, Dziegiel P, Dolinska-Krajewska B, Dumanska M, Cegielski M, Jethon Z, Rossini K, Carraro U, Zabel M (2006) Expression of metallothionein in renal tubules of rats exposed to acute and endurance exercise. Folia Histochem Cytobiol 44(3):195–200
Potts RJ, Bespalov IA, Wallace SS, Melamede RJ, Hart BA (2001) Inhibition of oxidative DNA repair in cadmium-adapted alveolar epithelial cells and the potential involvement of metallothionein. Toxicology 161(1–2):25–38
Powell SR (2000) The antioxidant properties of zinc. J Nutr 130(5S Suppl):1447S–1454S
Pula B, Domoslawski P, Podhorska-Okolow M, Dziegiel P (2012) Role of metallothioneins in benign and malignant thyroid lesions. Thyroid Res 5(1):26
Qu W, Diwan BA, Liu J, Goyer RA, Dawson T, Horton JL, Cherian MG, Waalkes MP (2002) The metallothionein-null phenotype is associated with heightened sensitivity to lead toxicity and an inability to form inclusion bodies. Am J Pathol 160(3):1047–1056
Quaife CJ, Findley SD, Erickson JC, Froelick GJ, Kelly EJ, Zambrowicz BP, Palmiter RD (1994) Induction of a new metallothionein isoform (MT-IV) occurs during differentiation of stratified squamous epithelia. Biochemistry 33(23):7250–7259
Quesada AR, Byrnes RW, Krezoski SO, Petering DH (1996) Direct reaction of H2O2 with sulfhydryl groups in HL-60 cells: zinc-metallothionein and other sites. Arch Biochem Biophys 334(2):241–250
Rana U, Kothinti R, Meeusen J, Tabatabai NM, Krezoski S, Petering DH (2008) Zinc binding ligands and cellular zinc trafficking: apo-metallothionein, glutathione, TPEN, proteomic zinc, and Zn-Sp1. J Inorg Biochem 102(3):489–499
Rani A, Kumar A, Lal A, Pant M (2014) Cellular mechanisms of cadmium-induced toxicity: a review. Int J Environ Health Res 24(4):378–399
Regunathan A, Glesne DA, Wilson AK, Song J, Nicolae D, Flores T, Bhattacharyya MH (2003) Microarray analysis of changes in bone cell gene expression early after cadmium gavage in mice. Toxicol Appl Pharmacol 191(3):272–293
Roesijadi G, Bogumil R, Vasak M, Kagi JH (1998) Modulation of DNA binding of a tramtrack zinc finger peptide by the metallothionein-thionein conjugate pair. J Biol Chem 273(28):17425–17432
Romero-Isart N, Vasak M (2002) Advances in the structure and chemistry of metallothioneins. J Inorg Biochem 88(3–4):388–396
Sabolic I (2006) Common mechanisms in nephropathy induced by toxic metals. Nephron Physiol 104(3):p107–114
Sabolic I, Breljak D, Skarica M, Herak-Kramberger CM (2010) Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. Biometals 23(5):897–926
Saito C, Yan HM, Artigues A, Villar MT, Farhood A, Jaeschke H (2010) Mechanism of protection by metallothionein against acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 242(2):182–190
Sakurai A, Hara S, Okano N, Kondo Y, Inoue J, Imura N (1999) Regulatory role of metallothionein in NF-kappaB activation. FEBS Lett 455(1–2):55–58
Santon A, Formigari A, Albergoni V, Irato P (2006) Effect of Zn treatment on wild type and MT-null cell lines in relation to apoptotic and/or necrotic processes and on MT isoform gene expression. Biochim Biophys Acta 1763(3):305–312
Sato M, Kondoh M (2002) Recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals. Tohoku J Exp Med 196(1):9–22
Saydam N, Adams TK, Steiner F, Schaffner W, Freedman JH (2002) Regulation of metallothionein transcription by the metal-responsive transcription factor MTF-1: identification of signal transduction cascades that control metal-inducible transcription. J Biol Chem 277(23):20438–20445
Schlake T, Boehm T (2001) Expression domains in the skin of genes affected by the nude mutation and identified by gene expression profiling. Mech Dev 109(2):419–422
Schuhmacher-Wolz U, Dieter HH, Klein D, Schneider K (2009) Oral exposure to inorganic arsenic: evaluation of its carcinogenic and non-carcinogenic effects. Crit Rev Toxicol 39(4):271–298
Schwarz MA, Lazo JS, Yalowich JC, Allen WP, Whitmore M, Bergonia HA, Tzeng E, Billiar TR, Robbins PD, Lancaster JR Jr et al (1995) Metallothionein protects against the cytotoxic and DNA-damaging effects of nitric oxide. Proc Natl Acad Sci USA 92(10):4452–4456
Shimoda R, Achanzar WE, Qu W, Nagamine T, Takagi H, Mori M, Waalkes MP (2003) Metallothionein is a potential negative regulator of apoptosis. Toxicol Sci 73(2):294–300
Simpkins C, Lloyd T, Li S, Balderman S (1998) Metallothionein-induced increase in mitochondrial inner membrane permeability. J Surg Res 75(1):30–34
Smaoui-Damak W, Berthet B, Hamza-Chaffai A (2009) In situ potential use of metallothionein as a biomarker of cadmium contamination in Ruditapes decussatus. Ecotoxicol Environ Saf 72(5):1489–1498
Smith E, Drew PA, Tian ZQ, De Young NJ, Liu JF, Mayne GC, Ruszkiewicz AR, Watson DI, Jamieson GG (2005) Metallothionien 3 expression is frequently down-regulated in oesophageal squamous cell carcinoma by DNA methylation. Mol Cancer 4:42
Smith DJ, Jaggi M, Zhang W, Galich A, Du C, Sterrett SP, Smith LM, Balaji KC (2006) Metallothioneins and resistance to cisplatin and radiation in prostate cancer. Urology 67(6):1341–1347
Stennard FA, Holloway AF, Hamilton J, West AK (1994) Characterisation of six additional human metallothionein genes. Biochim Biophys Acta 1218(3):357–365
Surowiak P, Kaplenko I, Spaczynski M, Zabel M (2003) The expression of metallothionein (MT) and proliferation intensity in ovarian cancers treated with cisplatin and paclitaxel. Folia Morphol (Warsz) 62(4):493–495
Surowiak P, Materna V, Maciejczyk A, Pudelko M, Markwitz E, Spaczynski M, Dietel M, Zabel M, Lage H (2007) Nuclear metallothionein expression correlates with cisplatin resistance of ovarian cancer cells and poor clinical outcome. Virchows Arch 450(3):279–285
Suzuki JS, Nishimura N, Zhang B, Nakatsuru Y, Kobayashi S, Satoh M, Tohyama C (2003) Metallothionein deficiency enhances skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate in metallothionein-null mice. Carcinogenesis 24(6):1123–1132
Suzuki-Kurasaki M, Okabe M, Kurasaki M (1997) Copper-metallothionein in the kidney of macular mice: a model for Menkes disease. J Histochem Cytochem 45(11):1493–1501
Szelachowska J, Dziegiel P, Jelen-Krzeszewska J, Jelen M, Tarkowski R, Wlodarska I, Spytkowska B, Gisterek I, Matkowski R, Kornafel J (2008) Prognostic significance of nuclear and cytoplasmic expression of metallothioneins as related to proliferative activity in squamous cell carcinomas of oral cavity. Histol Histopathol 23(7):843–851
Takahashi Y, Ogra Y, Suzuki KT (2005) Nuclear trafficking of metallothionein requires oxidation of a cytosolic partner. J Cell Physiol 202(2):563–569
Takano H, Inoue K, Yanagisawa R, Sato M, Shimada A, Morita T, Sawada M, Nakamura K, Sanbongi C, Yoshikawa T (2004) Protective role of metallothionein in acute lung injury induced by bacterial endotoxin. Thorax 59(12):1057–1062
Thornalley PJ, Vasak M (1985) Possible role for metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim Biophys Acta 827(1):36–44
Tio L, Villarreal L, Atrian S, Capdevila M (2004) Functional differentiation in the mammalian metallothionein gene family: metal binding features of mouse MT4 and comparison with its paralog MT1. J Biol Chem 279(23):24403–24413
Tio L, Villarreal L, Atrian S, Capdevila M (2006) The Zn- and Cd-clusters of recombinant mammalian MT1 and MT4 metallothionein domains include sulfide ligands. Exp Biol Med (Maywood) 231(9):1522–1527
Tokar EJ, Diwan BA, Waalkes MP (2010) Early life inorganic lead exposure induces testicular teratoma and renal and urinary bladder preneoplasia in adult metallothionein-knockout mice but not in wild type mice. Toxicology 276(1):5–10
Tsujikawa K, Imai T, Kakutani M, Kayamori Y, Mimura T, Otaki N, Kimura M, Fukuyama R, Shimizu N (1991) Localization of metallothionein in nuclei of growing primary cultured adult rat hepatocytes. FEBS Lett 283(2):239–242
Uchida Y (1994) Growth-inhibitory factor, metallothionein-like protein, and neurodegenerative diseases. Biol Signals 3(4):211–215
Uchida Y, Tomonaga M (1989) Neurotrophic action of Alzheimer's disease brain extract is due to the loss of inhibitory factors for survival and neurite formation of cerebral cortical neurons. Brain Res 481(1):190–193
Uchida Y, Takio K, Titani K, Ihara Y, Tomonaga M (1991) The growth inhibitory factor that is deficient in the Alzheimer's disease brain is a 68 amino acid metallothionein-like protein. Neuron 7(2):337–347
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M (2006) Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact 160(1):1–40
Vasak M (2005) Advances in metallothionein structure and functions. J Trace Elem Med Biol 19(1):13–17
Vasak M, Meloni G (2011) Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem 16(7):1067–1078
Waalkes MP, Harvey MJ, Klaassen CD (1984) Relative in vitro affinity of hepatic metallothionein for metals. Toxicol Lett 20(1):33–39
Waalkes MP, Liu J, Kasprzak KS, Diwan BA (2006) Hypersusceptibility to cisplatin carcinogenicity in metallothionein-I/II double knockout mice: production of hepatocellular carcinoma at clinically relevant doses. Int J Cancer 119(1):28–32
Werynska B, Pula B, Muszczynska-Bernhard B, Piotrowska A, Jethon A, Podhorska-Okolow M, Dziegiel P, Jankowska R (2011) Correlation between expression of metallothionein and expression of Ki-67 and MCM-2 proliferation markers in non-small cell lung cancer. Anticancer Res 31(9):2833–2839
Werynska B, Pula B, Muszczynska-Bernhard B, Gomulkiewicz A, Jethon A, Podhorska-Okolow M, Jankowska R, Dziegiel P (2013a) Expression of metallothionein-III in patients with non-small cell lung cancer. Anticancer Res 33(3):965–974
Wilhelmsen TW, Olsvik PA, Hansen BH, Andersen RA (2002) Evidence for oligomerization of metallothioneins in their functional state. J Chromatogr A 979(1–2):249–254
Wojnar A, Pula B, Piotrowska A, Jethon A, Kujawa K, Kobierzycki C, Rys J, Podhorska-Okolow M, Dziegiel P (2011) Correlation of intensity of MT-I/II expression with Ki-67 and MCM-2 proteins in invasive ductal breast carcinoma. Anticancer Res 31(9):3027–3033
Xia N, Liu L, Yi X, Wang J (2009) Studies of interaction of tumor suppressor p53 with apo-MT using surface plasmon resonance. Anal Bioanal Chem 395(8):2569–2575
Yang Y, Maret W, Vallee BL (2001) Differential fluorescence labeling of cysteinyl clusters uncovers high tissue levels of thionein. Proc Natl Acad Sci USA 98(10):5556–5559
Yang F, Zhou M, He Z, Liu X, Sun L, Sun Y, Chen Z (2007) High-yield expression in Escherichia coli of soluble human MT2A with native functions. Protein Expr Purif 53(1):186–194
Yap X, Tan HY, Huang J, Lai Y, Yip GW, Tan PH, Bay BH (2009) Over-expression of metallothionein predicts chemoresistance in breast cancer. J Pathol 217(4):563–570
Youn J, Hwang SH, Ryoo ZY, Lynes MA, Paik DJ, Chung HS, Kim HY (2002) Metallothionein suppresses collagen-induced arthritis via induction of TGF-beta and down-regulation of proinflammatory mediators. Clin Exp Immunol 129(2):232–239
Yu J, Fujishiro H, Miyataka H, Oyama TM, Hasegawa T, Seko Y, Miura N, Himeno S (2009) Dichotomous effects of lead acetate on the expression of metallothionein in the liver and kidney of mice. Biol Pharm Bull 32(6):1037–1042
Zalups RK, Ahmad S (2003) Molecular handling of cadmium in transporting epithelia. Toxicol Appl Pharmacol 186(3):163–188
Zamirska A, Matusiak L, Dziegiel P, Szybejko-Machaj G, Szepietowski JC (2012) Expression of metallothioneins in cutaneous squamous cell carcinoma and actinic keratosis. Pathol Oncol Res 18(4):849–855
Zangger K, Shen G, Oz G, Otvos JD, Armitage IM (2001) Oxidative dimerization in metallothionein is a result of intermolecular disulphide bonds between cysteines in the alpha-domain. Biochem J 359(Pt 2):353–360
Zbinden S, Wang J, Adenika R, Schmidt M, Tilan JU, Najafi AH, Peng X, Lassance-Soares RM, Iantorno M, Morsli H, Gercenshtein L, Jang GJ, Epstein SE, Burnett MS (2010) Metallothionein enhances angiogenesis and arteriogenesis by modulating smooth muscle cell and macrophage function. Arterioscler Thromb Vasc Biol 30(3):477–482
Zeng J, Heuchel R, Schaffner W, Kagi JH (1991a) Thionein (apometallothionein) can modulate DNA binding and transcription activation by zinc finger containing factor Sp1. FEBS Lett 279(2):310–312
Zeng J, Vallee BL, Kagi JH (1991b) Zinc transfer from transcription factor IIIA fingers to thionein clusters. Proc Natl Acad Sci USA 88(22):9984–9988
Zheng H, Liu J, Choo KH, Michalska AE, Klaassen CD (1996a) Metallothionein-I and -II knock-out mice are sensitive to cadmium-induced liver mRNA expression of c-jun and p53. Toxicol Appl Pharmacol 136(2):229–235
Zheng H, Liu J, Liu Y, Klaassen CD (1996b) Hepatocytes from metallothionein-I and II knock-out mice are sensitive to cadmium- and tert-butylhydroperoxide-induced cytotoxicity. Toxicol Lett 87(2–3):139–145
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Dziegiel, P., Pula, B., Kobierzycki, C., Stasiolek, M., Podhorska-Okolow, M. (2016). Metallothioneins: Structure and Functions. In: Metallothioneins in Normal and Cancer Cells. Advances in Anatomy, Embryology and Cell Biology, vol 218. Springer, Cham. https://doi.org/10.1007/978-3-319-27472-0_2
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