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Cellular zinc sensors: MTF-1 regulation of gene expression

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Abstract

Zinc metabolism in higher eukaryotes is complex, being controlled by uptake, efflux, and storage in individual cells, as well as in peripheral tissues and organs. Recently there have been advances in the understanding of the genes involved in these processes and their regulation. Metal-response element-binding transcription factor-1 (MTF-1) functions as a cellular zinc sensor which coordinates the expression of genes involved in zinc homeostasis, as well as protection against metal toxicity and oxidative stresses. In mice, these are known to include the metallothionein (MT), the zinc-transporter-1 (ZnT1) and the γ-glutamylcysteine synthetase heavy chain (γGCShc) genes. The cysteine-rich MTs function as an intracellular metal-chelators that bind zinc with high affinity, whereas the transmembrane protein ZnT1 exports zinc from the cell. γ-Glutamylcysteine synthetase controls the rate limiting step in glutathione (GSH) biosynthesis. GSH, which is present in mM concentrations in cells, effectively chelates large amounts of zinc in vitro. Both MT and GSH also function as antioxidants. The current model suggests that the zinc-finger domain of MTF-1 directly (and reversibly) binds to zinc. This metalloregulatory protein then adopts a DNA-binding conformation and translocates to the nucleus, where it binds to metal-response elements in these gene promoters leading to increased transcription. The six zinc-finger domain of this factor is highly conserved from insects to mammals, and biochemical studies confirm that the zinc-fingers are heterogeneous in function and in zinc-binding. Furthermore, the mouse MTF-1 gene is essential for development of the embryo, thus underscoring the importance of this transcription factor.

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References

  • Anderson ME. 1998 Glutathione: an overview of biosynthesis and modulation. Chem Biol Interact 111-112, 1-14.

    Google Scholar 

  • Andrews GK. 1990 Regulation of metallothionein gene expression. Prog Food Nutr Sci 14, 193-258.

    Google Scholar 

  • Andrews GK. 2000 Regulation of metallothionein gene expression by oxidative stress and metal ions. Biochem Pharm 59, 95-104.

    Google Scholar 

  • Andrews GK, Adamson ED. 1987 Butyrate selectively activates the metallothionein gene in teratocarcinoma cells and induces hypersensitivity to metal induction. Nucl Acids Res 15, 5461-5475.

    Google Scholar 

  • Andrews GK, Geiser J. 1999 Expression of metallothionein-I and-II genes provides a reproductive advantage during maternal dietary zinc deficiency. J Nutr 129, 1643-1648.

    Google Scholar 

  • Andrews GK, Lee DK, Ravindra R, Lichtlen P, Sirito M, Sawadogo M, Schaffner W. 2001 The transcription factors MTF-1 and USF1 regulate mouse metallothionein-I gene expression in visceral endoderm cells during early development. EMBO J. 20, 1114-1122.

    Google Scholar 

  • Auf der Maur A, Belser T, Elgar G, Georgiev O, Schaffner W. 1999 Characterization of the transcription factor MTF-1 from the Japanese pufferfish (Fugu rubripes) reveals evolutionary conservation of heavy metal stress response. Biol Chem 380, 175-185.

    Google Scholar 

  • Ballatori N. 1994 Glutathione mercaptides as transport forms of metals. Adv Pharmacol 27, 271-298.

    Google Scholar 

  • Bittel D, Dalton T, Samson S, Gedamu L, Andrews GK. 1998 The DNA-binding activity of metal response element-binding transcription factor-1 is activated in vivo and in vitro by zinc, but not by other transition metals. J Biol Chem 273, 7127-7133.

    Google Scholar 

  • Bittel D, Smirnova I, Andrews GK. 2000 Functional heterogeneity in the zinc fingers of the metalloregulatory transcription factor,MTF-1. J Biol Chem 275, 37194-37201.

    Google Scholar 

  • Brugnera E, Georgiev O, Radtke F, Heuchel R, Baker E, Sutherland GR, Schaffner W. 1994 Cloning, chromosomal mapping and characterization of the human metal-regulatory transcription factor MTF-1. Nucl Acids Res 22, 3167-3173.

    Google Scholar 

  • Chaberek S, Martell AE. 1959 Organic Sequestering Agents. New York: Wiley and Sons Inc.

    Google Scholar 

  • Chen XH, Agarwal A, Giedroc DP. 1998 Structural and functional heterogeneity among the zinc fingers of human MRE-binding transcription factor-1. Biochemistry 37, 11152-11161.

    Google Scholar 

  • Chen XH, Chu MH, Giedroc DP. 1999 MRE-binding transcription factor-1: Weak zinc-binding finger domains 5 and 6 modulate the structure, affinity, and specificity of the metal-response element complex. Biochemistry 38, 12915-12925.

    Google Scholar 

  • Cherian MG, Apostolova MD. 2000 Nuclear localization of metallothionein during cell proliferation and differentiation. Cell Mol Biol 46, 347-356.

    Google Scholar 

  • Cizewski Culotta V, Hamer DH. 1989 Fine mapping of a mouse metallothionein gene metal response element. Mol Cell Biol 9, 1376-1380.

    Google Scholar 

  • Cole TB, Wenzel HJ, Kafer KE, Schwartzkroin PA, Palmiter RD. 1999 Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene. Proc Natl Acad Sci USA 96, 1716-1721.

    Google Scholar 

  • Da Costa Ferreira AM, Ciriolo MR, Marcocci L, Rotilio G. 1993 Copper(I) transfer into metallothionein mediated by glutathione. Biochem J 292, 673-676.

    Google Scholar 

  • Dalton TD, Bittel D, Andrews GK. 1997 Reversible activation of the mouse metal response element-binding transcription factor-1 DNA binding involves zinc interactions with the zinc-finger domain. Mol Cell Biol 17, 2781-2789.

    Google Scholar 

  • Dalton TP, Fu K, Palmiter RD, Andrews GK. 1996a Transgenic mice that over-express metallothionein-I resist dietary zinc de-ficiency. J Nutr 126, 825-833.

    Google Scholar 

  • Dalton TP, Li QW, Bittel D, Liang LC, Andrews GK. 1996b Oxidative stress activates metal-responsive transcription factor-1 binding activity-Occupancy in vivo of metal response elements in the metallothionein-I gene promoter. J Biol Chem 271, 26233-26241.

    Google Scholar 

  • Dalton TP, Solis WA, Nebert DW, Carvan MJ, III. 2000 Characterization of the MTF-1 transcription factor from zebrafish and trout cells. Comp Biochem Physiol [B] 126, 325-335.

    Google Scholar 

  • Davis SR, McMahon RJ, Cousins RJ. 1998 Metallothionein knockout and transgenic mice exhibit altered intestinal processing of zinc with uniform zinc-dependent zinc transporter-1 expression. J Nutr 128, 825-831.

    Google Scholar 

  • Davis W, Jr., De Sousa PA, Schultz RM. 1996 Transient expression of translation initiation factor eIF-4C during the 2-cell stage of the preimplantation mouse embryo: Identification by mRNA differential display and the role of DNA replication in zygotic gene activation. Dev Biol 174, 190-201.

    Google Scholar 

  • DeMoor JM, Koropatnick DJ. 2000 Metals and cellular signaling in mammalian cells. Cell Mol Biol 46, 367-381.

    Google Scholar 

  • Griffith OW. 1999 Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radic Biol Med 27, 922-935.

    Google Scholar 

  • Griffith OW, Mulcahy RT. 1999 The enzymes of glutathione synthesis: gamma-glutamylcysteine synthetase. Adv Enzymol Relat Areas Mol Biol 73, 209-267.

    Google Scholar 

  • Günes Ç, Heuchel R, Georgiev O, Müller KH, Lichtlen P, Blüthmann 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, 2846-2854.

    Google Scholar 

  • Heuchel R, Radtke F, Georgiev O, Stark G, Aguet M, Schaffner W. 1994 The transcription factor MTF-I is essential for basal and heavy metal-induced metallothionein gene expression. EMBO J 13, 2870-2875.

    Google Scholar 

  • Huang LP, Gitschier J. 1997 A novel gene involved in zinc transport is deficient in the lethal milk mouse. Nature Genet 17, 292-297.

    Google Scholar 

  • Jensen LT, Howard WR, Strain JJ, Winge DR, Culotta VC. 1996 Enhanced effectiveness of copper ion buffering by CUP1 metallothionein compared with CRS5 metallothionein in Saccharomyces cerevisiae. J Biol Chem 271, 18514-18519.

    Google Scholar 

  • Kägi JHR, Schäffer A. 1988 Biochemistry of metallothionein. Biochemistry 27, 8509-8515.

    Google Scholar 

  • Kägi JHR. 1991 Overview of metallothionein. Methods Enzymol 205, 613-626.

    Google Scholar 

  • Karin M, Najarian R, Haslinger A, Valenzuela P, Welch J, Fogel S. 1984 Primary structure and transcription of an amplified genetic locus: the CUP1 locus of yeast. Proc Natl Acad Sci USA 81, 337-341.

    Google Scholar 

  • Klaassen CD, Liu J, Choudhuri S. 1999 Metallothionein: An intracellular protein to protect against cadmium toxicity. Annu Rev Pharmacol Toxicol 39, 267-294.

    Google Scholar 

  • Koizumi S, Suzuki K, Ogra Y, Gong P, Otsuka F. 2000 Roles of zinc fingers and other regions of the transcription factor human MTF-1 in zinc-regulated DNA binding. J Cell Physiol 185, 464-472.

    Google Scholar 

  • 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, 635-642.

    Google Scholar 

  • Koizumi S, Yamada H, Suzuki K, Otsuka F. 1992 Zinc-specific activation of a HeLa cell nuclear protein which interacts with a metal responsive element of the human metallothionein-IIA gene. Eur J Biochem 210, 555-560.

    Google Scholar 

  • 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, 34803-34809.

    Google Scholar 

  • Lazo JS, Kondo Y, Dellapiazza D, Michalska AE, Choo KHA, Pitt BR. 1995 Enhanced sensitivity to oxidative stress in cultured embryonic cells from transgenic mice deficient in metallothionein I and II genes. J Biol Chem 270, 5506-5510.

    Google Scholar 

  • Lazo JS, Kuo SM, Woo ES, Pitt BR. 1998 The protein thiol metallothionein as an antioxidant and protectant against antineoplastic drugs. Chem Biol Interact 112, 255-262.

    Google Scholar 

  • Li QW, Hu NM, Daggett MAF, Chu WA, Bittel D, Johnson JA, Andrews GK. 1998 Participation of upstream stimulatory factor (USF) in cadmium-induction of the mouse metallothionein-I gene. Nucl Acids Res 26, 5182-5189.

    Google Scholar 

  • Lichtlen P, Georgiev O, Schaffner W, Aguzzi A, Brandner S. 1999 The heavy metal-responsive transcription factor-1 (MTF-1) is not required for neural differentiation. Biol Chem 380, 711-715.

    Google Scholar 

  • Lieberman MW, Beach LR, Palmiter RD. 1983 Ultraviolet radiation-induced metallothionein-I gene activation is associated with extensive DNA demethylation. Cell 35, 207-214.

    Google Scholar 

  • Lu SC. 1999 Regulation of hepatic glutathione synthesis: current concepts and controversies. FASEB J 13, 1169-1183.

    Google Scholar 

  • Lu ZH, Cobine P, Dameron CT, Solioz M. 1999 How cells handle copper: A view from microbes. J Trace Elem Exp Med 12, 347-360.

    Google Scholar 

  • Maret W. 1994 Oxidative metal release from metallothionein via zinc-thiol/disulfide interchange. Proc Natl Acad Sci USA 91, 237-241.

    Google Scholar 

  • Maroni G, Ho AS, Laurent T. 1995 Genetic control of cadmium tolerance in Drosophila melanogaster. Environ Health Perspect 103, 1116-1118.

    Google Scholar 

  • Masters BA, Kelly EJ, Quaife CJ, Brinster RL, Palmiter, RD. 1994 Targeted disruption of metallothionein I and II genes increases sensitivity to cadmium. Proc Natl Acad Sci USA 91, 584-588.

    Google Scholar 

  • McMahon RJ, Cousins RJ. 1998a Mammalian zinc transporters. J Nutr 128, 667-670.

    Google Scholar 

  • McMahon RJ, Cousins RJ. 1998b Regulation of the zinc transporter ZnT-1 by dietary zinc. Proc Natl Acad Sci USA 95, 4841-4846.

    Google Scholar 

  • Mehra RK, Winge DR. 1991 Metal ion resistance in fungi: Molecular mechanisms and their regulated expression. J Cell Biochem 45, 30-40.

    Google Scholar 

  • Michalska AE, Choo KHA. 1993 Targeting and germ-line transmission of a null mutation at the metallothionein I and II loci in mouse. Proc Natl Acad Sci USA 90, 8088-8092.

    Google Scholar 

  • Miles AT, Hawksworth GM, Beattie JH, Rodilla V. 2000 Induction, regulation, degradation, and biological significance of mammalian metallothioneins. Crit Rev Biochem Mol Biol 35, 35-70.

    Google Scholar 

  • Müller HP, Brugnera E, Georgiev O, Badzong M, Müller KH, Schaffner W. 1995 Analysis of the heavy metal-responsive transcription factor MTF-1 from human and mouse. Somat Cell Mol Genet 21, 289-297.

    Google Scholar 

  • Nordberg M, Nordberg GF. 2000 Toxicological aspects of metallothionein. Cell Mol Biol 46, 451-463.

    Google Scholar 

  • O'Halloran TV. 1993 Transition metals in control of gene expression [see comments]. Science 261, 715-725.

    Google Scholar 

  • Okajima A, Miyazawa K, Kitamura N. 1993 Characterization of the promoter region of the rat hepatocyte-growth-factor/scatterfactor gene. Eur J Biochem 213, 113-119.

    Google Scholar 

  • Otsuka F, Iwamatsu A, Suzuki K, Ohsawa M, Hamer DH, Koizumi S. 1994 Purification and characterization of a protein that binds to metal responsive elements of the human metallothionein IIA gene. J Biol Chem 269, 23700-23707.

    Google Scholar 

  • 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, 330-340.

    Google Scholar 

  • Palmiter RD. 1987 Molecular biology of metallothionein gene expression. Experientia Suppl 52, 63-80.

    Google Scholar 

  • Palmiter RD. 1994 Regulation of metallothionein genes by heavy metals appears to be mediated by a zinc-sensitive inhibitor that interacts with a constitutively active transcription factor, MTF-1. Proc Natl Acad Sci USA 91, 1219-1223.

    Google Scholar 

  • Palmiter RD. 1998 The elusive function of metallothioneins. Proc Natl Acad Sci USA 95, 8428-8430.

    Google Scholar 

  • Palmiter RD, Cole TB, Findley SD. 1996a ZnT-2, a mammalian protein that confers resistance to zinc by facilitating vesicular sequestration. EMBO J 15, 1784-1791.

    Google Scholar 

  • Palmiter RD, Cole TB, Quaife CJ, Findley SD. 1996b ZnT-3, a putative transporter of zinc into synaptic vesicles. Proc Natl Acad Sci USA 93, 14934-14939.

    Google Scholar 

  • Palmiter RD, Findley SD. 1995 Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBO J 14, 639-649.

    Google Scholar 

  • Radtke F, Georgiev O, Müller H-P, Brugnera E, Schaffner W. 1995 Functional domains of the heavy metal-responsive transcription regulator MTF-1. Nucl Acids Res 23, 2277-2286.

    Google Scholar 

  • Radtke F, Heuchel R, Georgiev O, Hergersberg M, Gariglio M, Dembic Z, Schaffner W. 1993 Cloned transcription factor MTF-1 activates the mouse metallothionein I promoter. EMBO J 12, 1355-1362.

    Google Scholar 

  • Radtke F, Hug M, Georgiev O, Matsuo K, Schaffner, W. 1996. Differential sensitivity of zinc finger transcription factors MTF-1, Sp1 and Krox-20 to CpG methylation of their binding sites. Biol Chem 377, 47-56.

    Google Scholar 

  • Rebar EJ, Greisman HA, Pabo CO. 1996 Phage display methods for selecting zinc finger proteins with novel DNA-binding specificities. Methods Enzymol 267, 129-149.

    Google Scholar 

  • Roesijadi G. 2000 Metal transfer as a mechanism for metallothionein-mediated metal detoxification. Cell Mol Biol 46, 393-405.

    Google Scholar 

  • Shartzer KL, Kage K, Sobieski RJ, Andrews GK. 1993 Evolution of avian metallothionein: DNA sequence analyses of the turkey metallothionein gene and metallothionein cDNAs from pheasant and quail. J Mol Evol 36, 255-262.

    Google Scholar 

  • Shi ZZ, Osei FJ, Kala G, Kala SV, Barrios RJ, Habib GM, Lukin DJ, Danney CM, Matzuk, MM, Lieberman MW. 2000 Glutathione synthesis is essential for mouse development but not for cell growth in culture. Proc Natl Acad Sci USA 97, 5101-5106.

    Google Scholar 

  • Smirnova IV, Bittel DC, Ravindra R, Jiang H, Andrews, GK. 2000 Zinc and cadmium can promote the rapid nuclear translocation of MTF-1. J Biol Chem 275, 9377-9384.

    Google Scholar 

  • Soltaninassab SR, Sekhar KR, Meredith MJ, Freeman ML. 2000 Multi-faceted regulation of gamma-glutamylcysteine synthetase. J Cell Physiol 182, 163-170.

    Google Scholar 

  • Stuart GW, Searle PF, Chen HY, Brinster RL, Palmiter RD. 1984 A 12-base-pair DNA motif that is repeated several times in metallothionein gene promoters confers metal regulation to a heterologous gene. Proc Natl Acad Sci USA 81, 7318-7322.

    Google Scholar 

  • Stuart GW, Searle PF, Palmiter RD. 1985 Identification of multiple metal regulatory elements in mouse metallothionein-I promoter by assaying synthetic sequences. Nature 317, 828-831.

    Google Scholar 

  • Sugawara N, Sugawara C, Katakura M, Takahashi H, Mori M. 1991 Copper metabolism in the LEC rat: Involvement of induction of metallothionein and disposition of zinc and iron. Experientia 47, 1060-1063.

    Google Scholar 

  • Thiele DJ. 1992 Metal-regulated transcription in eukaryotes. Nucl Acids Res 20, 1183-1191.

    Google Scholar 

  • Tsuda M, Imaizumi K, Katayama T, Kitagawa K, Wanaka A, Tohyama M, Takagi T. 1997 Expression of zinc transporter gene, ZnT-1, is induced after transient forebrain ischemia in the gerbil. J Neurosci 17, 6678-6684.

    Google Scholar 

  • Vulpe CD, Packman S. 1995 Cellular copper transport. Annu Rev Nutr 15, 293-322.

    Google Scholar 

  • Wenzel HJ, Cole TB, Born DE, Schwartzkroin PA, Palmiter RD. 1997 Ultrastructral localization of zinc transporter-3 (ZnT-3) to synaptic vesicle membranes within mossy fiber boutons in the hippocampus of mouse and monkey. Proc Natl Acad Sci USA 94, 12676-12681.

    Google Scholar 

  • Wild AC, Mulcahy RT. 2000 Regulation of gammaglutamylcysteine synthetase subunit gene expression: insights into transcriptional control of antioxidant defenses. Free Radic Res 32, 281-301.

    Google Scholar 

  • Zhang B, Egli D, Georgiev O, Schaffner W. 2001 The Drosophila homolog of mammalian zinc-finger factor MTF-1 activates transcription in response to heavy metals. Mol Call Biol 21, 4505-4514.

    Google Scholar 

  • Zhao H, Eide DJ. 1997 Zap1p, a metalloregulatory protein involved in zinc-responsive transcriptional regulation in Saccharomyces cerevisiae. Mol Cell Biol 17, 5044-5052.

    Google Scholar 

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  1. Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, KS, 66160-7421, USA

    Glen K. Andrews

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Andrews, G.K. Cellular zinc sensors: MTF-1 regulation of gene expression. Biometals 14, 223–237 (2001). https://doi.org/10.1023/A:1012932712483

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