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Annals of Clinical & Laboratory Science 31:91-98 (2001)
© 2001 Association of Clinical Scientists

Presence of Potential Nickel-Responsive Element(s) in the Mouse MTH1 Promoter

Rongti Liang1, Hisato Igarashi2, Teruhisa Tsuzuki3, Yusaku Nakabeppu2,4, Mutsuo Sekiguchi5, Kazimierz S. Kasprzak1 and Yih-Horng Shiao1
1 Laboratory of Comparative Carcinogenesis, National Cancer Institute, Frederick, Maryland, USA
2 Department of Biochemistry, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
3 Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
4 CREST, Japan Science and Technology Corporation, Sawara-Ku, Fukuoka, Japan
5 Department of Biology and Frontier Research Center, Fukuoka Dental College, Fukuoka, Japan

Address correspondence to Yih-Horng Shiao, Ph.D., Building 538, Room 205, NCI-Frederick, Frederick, MD 21702, USA; tel 301 846 1246; fax 301 846 5946; e-mail shiao{at}mail.ncifcrf.gov.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
The murine MTH1 gene codes for MTH1, an 8-oxo-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase (8-oxo-dGTPase) which hydrolyzes 8-oxo-dGTP, a promutagenic product of reactive oxygen species’ attack on the nucleotide pool. This gene is regulated by oxidative stress. Therefore, we hypothesized that MTH1 expression can be affected by carcinogenic nickel(II), known to induce such stress. Three plasmid constructs, carrying different upstream regions of the mouse MTH1 and the chloramphenicol acetyltransferase (CAT) reporter gene, were transiently transfected into NIH 3T3 cells and the CAT protein was measured in nickel(II) acetate-treated and untreated cells. Nickel concentration-dependent increase of CAT protein level was observed for low Ni(II) concentrations, up to 400 µM Ni(II), in cells transfected with pHI103 plasmid (-5969 to +530 of the MTH1 sequence) only. Cells transfected with the pHI104 (-1331 to +530) or pHI108 (-151 to +530) plasmids did not respond to nickel(II) whatsoever. This finding demonstrated that the MTH1 sequence between -5969 and -1331 contained element(s) responsive to nickel(II) treatment. DNA sequencing revealed the presence of AP-1, NF-{kappa}B, and ATF-1 binding sites in both the -5969 to -1331 and -1331 to +530 regions. In contrast, two (CA)n repeats (-5642 to -5582 and -2078 to -2031), a family of B2 (-5428 to -5247) and B1 (-4559 to -4420) short interspersed repeated elements, and an (AT)n repeat (-5243 to -5230) were identified only in the -5969 to -1331 sequence. The results suggest that up-regulation of murine MTH1 expression by nickel(II) is controlled by the repeat sequences, potential candidates for nickel-responsive elements.

(received 12 October 2000; accepted 18 October 2000)

Keywords: nickel, MTH1 gene, promoter, responsive element, gene expression


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 
Nickel compounds are carcinogenic in humans and animals [1]. However, the underlying molecular mechanisms are still unclear. Certain natural complexes of nickel(II) are redox-active at physiological pH and may thus facilitate the generation of reactive oxygen species (ROS), which, in turn, can damage DNA and influence gene expression through various mechanisms [2,3]. Increased levels of 8-oxo-2'-deoxyguanosine (8-oxo-dG), a common marker for oxidative DNA damage, and other oxidized DNA bases have been observed in animals treated with nickel compounds [4–6]. The promutagenic 8-oxo-dG lesion may be generated in situ in DNA through a direct attack of ROS on chromatin, or incorporated into DNA from 8-oxo-dGTP produced by ROS in the deoxynucleotide pool. In either case, this lesion leads to gene mutations by G to T or A to C transversion because of mispairing of 8-oxoguanine with adenine [7]. The mutagenicity of 8-oxo-dGTP far exceeds that of the in situ-generated 8-oxo-dG [7]. To eliminate 8-oxo-dGTP, mammalian cells are armed with a gene, named MTH1 in mice and hMTH1 in humans (analogues of the bacterial mutT gene), encoding an 8-oxo-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase (8-oxo-dGTPase) which hydrolyzes 8-oxo-dGTP directly to 8-oxo-dGMP [8,9]. Thus, activation of 8-oxo-dGTPase expression by ROS, reported previously [10], is important for the prevention of mutations and carcinogenesis by nickel exposure.

Differential expression of several genes has been observed in cells treated with nickel compounds [11–15]. Thus far, all known nickel effects on gene expression seem to be indirect and modulated by transcription factors. For example, nickel(II)-induced increase of ATF-1 transcription factor negatively regulates thrombospondin 1 expression [12], and the induction of Cap43 expression by nickel(II) treatment is dependent on the presence of HIF-1 transcription factor [14]. Nickel(II)-mediated DNA methylation, another indirect nickel control, has been also shown to silence expression of the gpt gene [16]. In contrast, elements modulating gene expression which would be regulated by nickel(II) directly have not yet been found. Although the metal-responsive element of the metallothionein-IIA gene and the heat shock element of the hsp70 gene respond directly to several metals, nickel(II) appears to have no effect on these two elements [17].

The responsiveness of the MTH1 gene to nickel-associated ROS or, perhaps, to nickel itself has not been established. To test the hypothesis that nickel(II) has a potency to regulate MTH1 expression, and to determine the direct or indirect mechanism of this regulation, different regions of the upstream MTH1 gene were examined to localize segment(s) responsive to nickel(II)-dependent expression control. Homologous gene sequence(s) and transcription factor binding consensus sequence(s) were analyzed using computer programs.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Acknowledgements
 References
 
Chemicals.  Nickel(II) acetate tetrahydrate was purchased from J. T. Baker Co. (Phillipsburg, NJ). The other chemicals were from Sigma Chemical Co. (St. Louis, MO), unless specified otherwise.

Plasmids and DNA transfection.  Plasmids carrying the MTH1 upstream sequences (pHI103: nucleotides -5969 to +530; pHI104: nucleotides -1331 to +530; and pHI108: nucleotides -151 to +530) and the chloramphenicol acetyltransferase (CAT) reporter gene, described previously [18], were used as transfectants. NIH 3T3 mouse fibroblast cells were cultured in 12.5 x 8.5 cm 6-well plates (35 mm in diameter x 18 mm deep wells) with 3 ml of Dulbecco’s Modified Eagle’s medium (DMEM) supplemented with 10% fetal bovine serum per well, in a humidified atmosphere of 5% CO2 at 37°C. Three hundred thousand cells were seeded in a single well. After 24-hr incubation, when the cells reached approximately 50% confluence, Lipofectamine Plus reagent (Life Technologies, Gaithersburg, MD) was used to transfect the cells with 2 µg of plasmid according to the manufacturer’s instructions.

Nickel(II) acetate treatment.  After DNA transfection for 3 to 5 hr, the reagent was replaced with 3.65 ml pre-warmed DMEM containing 13% fetal bovine serum and the cells were incubated at 37°C for another 20 hr. Aliquots of 10 mM or 100 mM nickel(II) acetate stock solution in water were then added to the cells to make the final nickel concentrations in DMEM ranging from 0 to 1000 µM. No attenuation in the cell growth, or viable cell loss below 5%, were observed up to 200 µM Ni(II). Above that concentration, the number of detached (floating) cells increased gradually from approximately 10% at 400 µM to more than 60% at 1000 µM Ni(II) in 20 hr, indicating a concurrent increase in the metal toxicity. After 20-hr incubation with nickel(II), the attached cells were analyzed for CAT protein as described below.

Quantification of CAT protein expression.  The culture medium was removed, the cells were rinsed twice with 2 ml portions of PBS, and finally lysed in 225 µl of 1x CAT Lysis Buffer (Boehringer Mannheim, Indian-apolis, IN) with shaking for 20 min at room temperature. Aliquots of 2.5 µl of the lysate were transferred into a 96-well microplate for total protein determination by the bicinchoninic acid method, using a kit (Pierce, Rockford, IL). The remaining lysate was used for CAT protein measurements with the CAT ELISA immunoassay kit (Boehringer Mannheim, Indian-apolis, IN), according to the producer’s protocol. The relative CAT protein expression was calculated as the ratio of CAT concentration to total protein.

Statistical analysis.  Each treatment was repeated at least 3 times. The t-test was used to determine the difference of CAT protein level among treatments. Analysis of trend was carried out using linear regression statistics. Differences between means or slopes with p values <0.05 were considered statistically significant.

DNA sequencing and computer analysis.  The ABI Prism Dye Terminator Cycle Sequencing Kit and ABI 373 automatic DNA sequencer (Perkin-Elmer Applied Biosystems, Foster City, CA) were used to determine DNA sequence. Potential homologous sequences in the MTH1 upstream region were searched using the Blast program available from the National Center for Biotechnology Information web site (http://www.ncbi.nlm.nih.gov) [19]. In the Advanced Blast, the default settings were applied except that the Filter function was inactivated to include sequences with low complexity and the Alignment was increased to maximize printout of the matched sequences. The Blast 2 Sequences program was used to determine similarity and identity between two sequences [20]. Transcription factor binding consensus sequences were examined using the Transfac program (version 4.0) at its web site (http://transfac.gbf.de) [21]. A match >80% to Genbank or Transfac databases was considered to be a homologous or consensus sequence.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Acknowledgements
 References
 
Nickel(II) concentration-dependent response of the pHI103 plasmid was detected (Fig. 1Go). A steady increase of CAT protein level was observed in pHI103-transfected cells treated with up to 400 µM nickel(II) acetate. Unfortunately, the concurrent increase in nickel(II) toxicity and the resulting marked loss of the transfected cells made CAT measurements for >400 µM nickel(II) unreliable. Although the differences between individual treatments were not significant, the trend of increase reached a significant level (p < 0.05). In contrast, treatments with non-toxic nickel(II) concentrations did not elicit any nickel(II)-dependent trends of increase or decrease of CAT protein levels in cells transfected with the pHI104 or pHI108 plasmids (Fig. 2Go). Treatment of higher nickel(II) concentration was therefore not performed.



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  		Fig, 1. Effects of nickel(II) on expression of the CAT reporter (y-axis) in pHI103-transfected cells (error bars, +1 SEM).

 


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  		Fig, 2. Effects of nickel(II) on expression of the CAT reporter (y-axis) in pHI104- and pHI108-transfected cells.

 
To examine what sequence(s) in the pHI103 plasmid might regulate the nickel(II)-dependent response, the MTH1 upstream sequence (position -5969 to -2354, flanked by XhoI and HindIII restriction sites) was determined by DNA sequencing (Fig. 3Go). The MTH1 sequence in pHI103 plasmid was then compared to the sequences in pHI104 and pHI108. Analyses of transcription factor binding motifs revealed that 31 of the 191 available motifs in the database were unique to the region of -5969 to -1331 (pHI103 plasmid) and 10 were only seen in the -1331 to +530 region (pHI104 and pHI108).



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  		Fig. 3 The MTH1 promoter sequence. Restriction sites (XhoI, KpnI, and HindIII) are indicated with solid underlines. Ap1, NF-{kappa}B, and ATF-1 transcription factor binding motifs are highlighted with dashlines. Newly determined sequence between -5969 and -1331 (XhoI-KpnI) was deposited in GenBank (Accession AF291054 [GenBank] ). The sequence from -2354 to +530 (KpnI-HindIII) in the pHI103 plasmid was published previously (Accession D88356 [GenBank] ). The MTH1 sequences of -3577 to -3146 and -943 to -732 (bold and italic) were matched to human FHJ1 cell division protein (GenBank accession AF093415 [GenBank] ) at 757 to 326 and 327 to 116 coding sequences, respectively. Bold and capital letters, from top to bottom, were (CA)n repeat, B2 element, (AT)n repeat, B1 element, and (CA)n repeat.

 
The widely-studied regulatory sequences, such as Ap1, NF-{kappa}B, and ATF-1 binding motifs, were observed numerously in both the -5969 to -1331 and -1331 to +530 regions. In Blast analysis, 2 (CA)n repeats (-5642 to -5582 and -2078 to -2031), a family of B2 (-5428 to -5247) and B1 (-4559 to -4420) short interspersed repeated elements (SINE), and a (AT)n repeat (-5243 to -5230) were detected in the -5969 to -1331 sequence, and the 5 repeat sequences distinguished clearly the region from the -1331 to +530 sequence (Fig. 3Go). The B1 element was truncated. The B2 element was a complete SINE sequence with poly-A tail. Blast analysis of the MTH1 upstream sequence discovered that antisense sequences of -5969 to -1331 and -1331 to +530 regions are homologous to the human FJH1 codons 224 to 81 and codons 80 to 11 sequences, respectively (Fig. 3Go). CpG island (CpG/ GpC >1) was not observed in the examined upstream sequence.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Acknowledgements
 References
 
The presence of regulatory sequence(s) responsive to nickel(II) in the pHI103 plasmid is demonstrated by the nickel(II) concentration-dependent elevation of the CAT reporter protein. It is not clear what contributed to only a moderate response, ie, the less-than-2-fold increase of the pHI103 plasmid responsiveness to nickel(II) treatment. Factors, such as cell loss, especially for cells carrying transfected plasmid, high CAT protein level in control cells, and treatment of nickel(II) for relatively short period of time (<20 hr), may account for this moderated nickel response. Comparison of the MTH1 sequence in nickel(II)-responsive pHI103 plasmid with those in the non-responsive pHI104 and pHI108 plasmids clearly indicates that the sequence(s) responsive to the metal are present in the region between -5969 and -1331 of the MTH1 gene.

Since cellular nickel(II) is capable of initiating redox reactions that lead to generation of ROS, it is possible that the observed response of pHI103 plasmid to this metal was triggered by oxidative stress. It has been shown, indeed, that nickel(II) increases cellular levels of the ATF-1 transcription factor [12] and regulates DNA binding of AP-1 and NR-{kappa}B transcription factors [22,23], which are sensitive to redox regulation [reviewed in ref 3]. However, in our transiently transfected cells, the positive response of the MTH1 -5969 to -1331 region to nickel(II) appears not to be associated solely with the Ap1, NF-{kappa}B, or ATF-1 because binding motifs of these transcription factors are present also in the nickel-unresponsive 1331 to +530 regions. Presence of the FJH1 homologue in antisense direction of the MTH1 upstream region is interesting. Further study is needed to determine if the FJH1 homologue is transcriptionally active and contributes to MTH1 expression regulation.

Other possibilities are that nickel(II) could regulate MTH1 expression by modulating cytosine methylation/demethylation processes, or by reacting directly with selected DNA base sequence(s) in the MTH1 -5969 to -1331, thus altering conformation of certain DNA region(s) and, in turn, gene expression. It has been shown that nickel(II) can regulate gene expression by affecting DNA methylation at CpG sites in the promoter region [16]. However, in the present study we did not detect any CpG island in the MTH1 promoter region (up to -5969). Therefore, the different nickel(II) responses between the pHI103 plasmid and the pHI104 and pHI108 plasmids are most likely not associated with global DNA methylation status, although the role of individual site is not excluded.

The remaining possibility of a direct nickel(II) action on DNA, mentioned above, that would be indicative of the presence of nickel(II)-responsive element(s) in pHI103 plasmid was explored by computer analysis. The resulting finding of many repeat sequences in the MTH1 -5659 to -1331 region was quite intriguing. The B1 and B2 elements found in pHI103, but not in the other two plasmids, belong to the SINE family in rodents, corresponding to Alu repeats in humans [24]. They function as retrotransposons transposed in the genome through RNA polymerase III-transcribed RNA intermediates during evolution [24]. Up-regulation of the B1 and B2 RNA levels has been observed in cells under various stress conditions [25,26]. Previously, we also observed differential expression of the B1- and B2-like RNA in nickel(II)-treated Chinese hamster ovary (CHO) cells [13; and unpublished data]. Double-stranded Alu RNA has been shown to enhance translation by inactivating PKR kinase and subsequently inhibiting phosphorylation of eIF2-alpha, a translation suppressor if phosphorylated [27]. It has been also reported that flanking of B2 elements in either sense or antisense orientation can influence gene expression [28]. These observations would provide at least a partial explanation of the observed nickel(II)-dependent increase of CAT reporter protein in pHI103-transfected cells. Possible association of the B2 element with nickel(II)-dependent MTH1 gene expression in the current study is interesting and needs to be investigated further, including elucidation of the underlying chemistry of nickel(II) interactions with these elements.

Direct interaction of nickel(II) and other metal ions with several synthetic double- and single-stranded DNAs, including poly d(A-C).d(G-T) and poly d(A-T), has been investigated previously [29–31]. This interaction promotes various types of conformational and structural transitions in DNA, including ultimately the switch from B to Z form [31]. Nickel(II) bound at the A-T base pairs is especially effective in stabilizing the syn conformation of the deoxyadenine residue and thus the Z conformation of DNA [30]. Presence of the (CA)n and (AT)n repeats in the MTH1 promoter region suggests that nickel(II)-dependent up-regulation of the CAT reporter protein in pHI103-transfected cells might be mediated by the direct interaction of nickel(II) with these repeat sequences and the subsequent DNA transitions. The B to Z transition was first observed in vitro for relatively high (>=100 µM) concentrations of the reagents [30]. However, as reported by Rosetto and Nieboer [31], the metal-induced effects on DNA structure are not limited to the B to Z transition. The structural changes develop gradually and are often multiphasic [biphasic for nickel(II)] with increasing metal concentration. The first detectable conformational alterations become apparent at much lower concentrations (about 10 µM) of the metal, and the final result depends more on the DNA:metal molar ratio and binding affinity than on the absolute concentration itself. Also, high local intra-cellular concentrations of nickel(II) seem to be feasible, especially in cells phagocytizing and solubilizing internally particulate nickel compounds [32]. Controlling the interconversion between the different structural forms of DNA may relax or condense the double-stranded DNA and in this way directly affect gene expression. Although the (CA)n repeat is abundant in mammalian genome, accessibility of the sequences to nickel(II) may be dependent on the topography during chromatin unwinding. Our concept of nickel(II) targeting the (CA)n and (AT)n repeats in DNA is consistent with the finding by Kawanishi et al [33] that nickel(II) mediates oxidative DNA cleavage preferably at cytosines and thymines (followed by guanines). This process requires generation of ROS site-specifically, ie, most likely by nickel(II) bound at these residues.

The relevance of the present finding to the mechanisms of nickel-induced carcinogenesis is, at this moment, difficult to ascertain. Further studies are necessary to dissect the MTH1 promoter regions and to confirm in different models the potential involvement of the repeat sequences in gene expression regulation by nickel(II) (and possibly other carcinogenic metals), reported here for the first time, and to pinpoint the most responsive one(s). Such a direct action of nickel(II) on gene expression was observed in this study only for low nickel(II) concentrations, which might not have induced a detectable oxidative stress [34]. This, however, does not exclude the possibility that at higher cellular nickel(II) concentrations [32], ROS could also contribute to up-regulation of MTH1 expression through redox-sensitive transcription factors, as observed by others in human cells exposed to hydrogen peroxide [10]. The latter response was limited to certain low concentrations of H202; highest concentrations tend to be inhibitory.

In conclusion, the presence of repeat sequences, including B1, B2, (CA)n, and (AT)n, in the MTH1 upstream region coincides with the nickel(II)-dependent response of gene expression. The results suggest that regulation of the MTH1 gene may be mediated in part by direct interaction of nickel(II) with these repeat sequences, putative nickel(II)-responsive elements.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
References
 
The skilled technical help of Robert M. Bare and John Elser, the invaluable critical comments of Dr. Gregory S. Buzard, and the editorial help of Ms. Kathleen R. Breeze are gratefully acknowledged.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Acknowledgements
 References
 

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