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Regulation of Metallothionein Genes by Heavy Metals Appears to Be

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Regulation of Metallothionein Genes by Heavy Metals Appears to Be Proc. Nati. Acad. Sci. USA Vol. 91, pp. 1219-1223, February 1994 Biochemistry 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 RICHARD D. PALMITER Howard Hughes Medical Institute and Department of Biochemistry, SL-15, University of Washington, Seattle, WA 98195 Contributed by Richard Palmiter, November 4, 1993 ABSTRACT A construct, MRE-PGeo, with five metal into cells along with a MRE-driven reporter gene, it resulted response elements fused to a selectable reporter gene was in constitutive expression of the reporter gene in the absence transfected into BHK cells and a stable clone that could be of added metal inducer (16). Thus, MTF-1 is a candidate induced up to 100-fold by zinc, cadmium, bismuth, silver, transcription factor for interaction with MREs, but it is not cobalt, copper, mercury, or nickle was isolated. Some, and clear how it is regulated by metals. The induction of mam- perhaps all, of these metals induce MRE-,Geo by displacing malian MTs by metals is compounded by the observation that zinc. Transfection of these cells with a construct encoding the a wide variety of metals are good inducers, including some transcriptional activator MTF-1 resulted in constitutive ex- metals that are not bound by MT (18). Hence, it is unclear pression of MRE-PGeo, whereas expression of an antisense whether all of these metals stimulate the same traiscription MTF-1 construct in these cells prevented induction by all ofthe factor and, if not, whether different metal-responsive tran- metals. A variant cell line with high conktitutive expression in scription factors recognize different cis-acting elements in the absence of added metals was isolated; normal regulation MT gene promoters. The cloning of MTF-1 (16) provides a was restored by cell fusion. These results suggest that regula- starting point for trying to unravel the regulation of mamma- tion of metallothionein genes by metals is mediated by MTF-1 lian MT genes. interacting with metal response elements and that zinc func- tions to release MTF-1 from an inhibitor. MATERIALS AND METHODS Plasmids. MRE-(3Geo. A BamHI-HindIII fragment con- Metallothionein (MT) genes have been described for a wide taining five MRE-d' elements (6) upstream ofthe basal mouse variety of organisms ranging from yeast to man. These genes MT-I promoter (-42 to +60) was introduced between the Not encode small, cysteine-rich, metal-binding proteins that pro- I and Hind]Il sites of /Geo, a f-galactosidase-neomycin vide protection against metal toxicity and may play a role in phosphotransferase (lacZ-neo) fusion gene (19). CMV- homeostasis ofessential metals (1, 2). There is alto mounting MTF-1. Two pairs of complementary oligonucleotides (25- evidence that they may help protect against reactive oxygen mers with 6 bp of overlap) were synthesized with sequences (3). MT gene expression is ugually inducible. For example, corresponding to the 5' and 3' ends of the published MTF-1 the mammalian MT-I and MT-II genes, which are expressed clone (16). Each oligonucleotide pair was filled in by using in most cells, are induced by a variety of metals, hoimones, DNA polymerase and [a-32P]dNTPs and then combined to and xenobiotics (1, 2, 4, 5). screen a A ZAP mouse brain cDNA library (Stratagene). Five Most MT genes that have been studied are inducible by of nine clones that were plaque-purified hybridized to both metals. Induction of mammalian MT genes by metals is the 5' and 3' probes; the longest one extends 18 bp further 5' mediated by short DNA elements called metal response than the published sequence (16). The Nco I fragment that elements (MREs) that are present in multiple copies in the includes the entire MTF-I open reading frame was inserted promoter region of these genes (5). For example, the mouse between a cytomegalovirus (CMV) promoter/enhancer and a MT-I gene has five functional MREs within the 150 bp simian virus 40 (SV40) polyadenylylation region of a cDNA flanking the transcription start site, but they are not all expression plasmid. Then, a Not I fragment containing the functionally equivalent (6, 7). Genomic footprinting of nuclei CMV-MTF-1-SV40 cassette was introduced into pNUT, a from induced and uninduced cells indicated that a factor is plasmid vector with a dihydrofolate reductase gene driven by bound to the MREs only during induction, suggesting that the SV40 promoter/enhancer (20). CMV-MTF(AZF). The metals allow a positively acting transcription factor to inter- regions encoding the zinc fingers were removed from the act with the MREs (8, 9). Proteins have been detected in construct described above by restriction with ApaLI, which nuclear extracts of mammalian cells that bind to radiolabeled cuts conveniently at the borders of the six fingers, and the MREs, but several different sizes for these proteins have reading frame was restored with an oligonucleotide linker. been reported and the effects of zinc, cadmium, and copper CMV-aMTF-1. When the 2.1-kb Nco I fragment containing on binding activity were variable; thus, the number of dif- the MTF-1 sequence was inserted into the CMV vector, both ferent factors capable of binding MREs is unclear (7, 10-15). orientations were obtained. The antisense orientation was Recently, a clone encoding a MRE-binding protein was moved into pNUT as described above. isolated from a cDNA expression library by using labeled Cells and Transfection. BHK cells (thymidine kinase- MREs as a probe (16). This protein, called MTF-1, has six negative, MT-) were grown in Dulbecco's modified Eagle's zinc fingers of the 2 Cys-2 His type and resembles transcrip- medium (DMEM) (Life Technologies, Gaithersburg, MD) tion factors with this motif (17). It can be isolated in an active plus 10o fetal bovine serum unless otherwise indicated. For form from uninduced cells. When the cDNA for this factor transfection, a calcium phosphate precipitate with 20 ug of was put under control ofa strong promoter and cotransfected plasmid DNA was applied to cells that were about 25% The publication costs of this article were defrayed in part by page charge Abbreviations: MT, metallothionein; MRE, metal response element; payment. This article must therefore be hereby marked "advertisement" CMV, cytomegalovirus; SV40, simian virus 40; PDC, pyrrolidine in accordance with 18 U.S.C. §1734 solely to indicate this fact. dithiocarbonate. 1219 Downloaded by guest on September 23, 2021 1220 Biochemistry: Palmiter Proc. Natl. Acad. Sci. USA 91 (1994) confluent on a 10-cm plate in 10 ml of medium along with 100 - ,uM chloroquine (21). The medium was changed 4 hr later. 4~~60 60- Cells were split the next day and selection with G418 (800 10t_-. 0 pg/ml) and ZnSO4 (80 pM) or methotrexate (200 pM) was begun. Individual colonies were picked with cloning rings (440 -40 0 about 2 weeks later and then expanded in selection medium for about a month. For some experiments, cells were grown /O in a specially formulated Opti-MEM (Life Technologies) that 0 C(/-'0 was prepared without zinc, Opti-MEMAZn. This medium contains <0.1 zinc compared with 1.0 pLM in normal MM 0 5 10 15 0 0.2 0.4 Q6 0.8 Opti-MEM. DMEM with 10%1 serum contains 3.8 pM zinc. Zinc (/M) Cadmium (pM) Metal concentrations were measured by inductively coupled plasma emission spectroscopy. FIG. 1. Induction of MIRE-,8Geo in cell line 3038-1-1 by zinc and The MRE-,BGeo clone 3038-1-1 was mutagenized six times cadmium. Cells were grown for 3 days in Opti-MEMAZn (e) or in the with ICR-191 (5-10 pg/ml for 2-4 hr) as described by same medium supplemented with 0.5 AM ZnS04 (o) and then the McKendry et aL (22). Then the cells were selected with G418 indicated concentrations of zinc (Left) or cadmium (Right) were at 3.2 mg/ml in the absence of zinc. Clones were picked 2 addedfor an additional 20 hrprior to assay/-galactosidaseof activity weeks later and tested individually for induction of MRE- [(A405 unit per pg of DNA) x 103]. (3Geo by zinc. One of the subclones (3286-8-8) was fused to a hygromycin-resistant clone of BHK cells by plating equal dose-response curves for zinc and cadmium induction of numbers of the two cell types and treating them with 50%1 M[EE-.BGeo in cells grown in Opti-MEMAZn with or without polyethylene glycol for 1 min (23) and then selecting for addition of 0.5 pM ZnS04. Note that these cells were less hybrids with G418 (800 pg/ml), hygromycin (800 pg/ml), and responsive to zinc when grown in synthetic medium contain- ZnSO4 (80 PM). ing 0.5 pM ZnS04 but more responsive to cadmium. The 3-Galactosidase Assay. Cells were trypsinized and plated in maximum extent of induction achieved with several other 24-well dishes 1-2 days before addition of inducers. Stock metals was tested under the same conditions (Fig. 2B) and in solutions of metals (CdSO4, ZnSO4, AgNO3, CuSO4, HgCl2, DMEM plus 10%o fetal bovine serum (Fig. 2A). The concen- bismuth ammonium citrate, CoCl2, NiCl2) or metal chelators tration ofeach metal that gave optimal induction is indicated were diluted about 100-fold into the tissue culture medium. above the bars in Fig. 2; for most metals, higher concentra- About 20 hr later the cells were fixed for 5 min in 0.2% glutaraldehyde and 2% formaldehyde in phosphate-buffered A 160-- saline at 4°C and then rinsed three times in phosphate- 140 3 12 fDMlENP-- C - S buffered saline.
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