{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T12:11:11Z","timestamp":1790424671956,"version":"4.1.0"},"reference-count":108,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,3,17]],"date-time":"2019-03-17T00:00:00Z","timestamp":1552780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Yorkshire Cancer Research","award":["Y003"],"award-info":[{"award-number":["Y003"]}]},{"name":"York Against Cancer","award":["Programme Grant"],"award-info":[{"award-number":["Programme Grant"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Occupational and environmental exposure to cadmium is associated with the development of urothelial cancer. The metallothionein (MT) family of genes encodes proteins that sequester metal ions and modulate physiological processes, including zinc homeostasis. Little is known about the selectivity of expression of the different MT isoforms. Here, we examined the effect of cadmium exposure on MT gene and isoform expression by normal human urothelial (NHU) cell cultures. Baseline and cadmium-induced MT gene expression was characterized by next-generation sequencing and RT-PCR; protein expression was assessed by Western blotting using isoform-specific antibodies. Expression of the zinc transporter-1 (SLC30A1) gene was also assessed. NHU cells displayed transcription of MT-2A, but neither MT-3 nor MT-4 genes. Most striking was a highly inducer-specific expression of MT-1 genes, with cadmium inducing transcription of MT-1A, MT-1G, MT-1H, and MT-1M. Whereas MT-1G was also induced by zinc and nickel ions and MT-1H by iron, both MT-1A and MT-1M were highly cadmium-specific, which was confirmed for protein using isoform-specific antibodies. Protein but not transcript endured post-exposure, probably reflecting sequestration. SLC30A1 transcription was also affected by cadmium ion exposure, potentially reflecting perturbation of intracellular zinc homeostasis. We conclude that human urothelium displays a highly inductive profile of MT-1 gene expression, with two isoforms identified as highly specific to cadmium, providing candidate transcript and long-lived protein biomarkers of cadmium exposure.<\/jats:p>","DOI":"10.3390\/ijms20061344","type":"journal-article","created":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T12:18:53Z","timestamp":1552911533000},"page":"1344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Specificity of the Metallothionein-1 Response by Cadmium-Exposed Normal Human Urothelial Cells"],"prefix":"10.3390","volume":"20","author":[{"given":"Rhiannon V.","family":"McNeill","sequence":"first","affiliation":[{"name":"Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, York Biomedical Research Institute, University of York, York YO10 5DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8222-3974","authenticated-orcid":false,"given":"Andrew S.","family":"Mason","sequence":"additional","affiliation":[{"name":"Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, York Biomedical Research Institute, University of York, York YO10 5DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8166-1526","authenticated-orcid":false,"given":"Mark E.","family":"Hodson","sequence":"additional","affiliation":[{"name":"Department of Environment and Geography, University of York, York YO10 5DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.F.","family":"Catto","sequence":"additional","affiliation":[{"name":"Academic Urology Unit, University of Sheffield, Sheffield S10 2TN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0135-480X","authenticated-orcid":false,"given":"Jennifer","family":"Southgate","sequence":"additional","affiliation":[{"name":"Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, York Biomedical Research Institute, University of York, York YO10 5DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,17]]},"reference":[{"key":"ref_1","first-page":"133","article-title":"Heavy Metals Toxicity and the Environment","volume":"101","author":"Tchounwou","year":"2012","journal-title":"EXS"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10561","DOI":"10.1007\/s11356-014-2970-0","article-title":"Cadmium as a possible cause of bladder cancer: A review of accumulated evidence","volume":"21","year":"2014","journal-title":"Environ. Sci. Pollut. Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.mrfmmm.2003.07.011","article-title":"Cadmium carcinogenesis","volume":"533","author":"Waalkes","year":"2003","journal-title":"Mutat. Res."},{"key":"ref_4","unstructured":"(2016, September 14). Agency for Toxic Substances and Disease Registry Toxicological Profile for Cadmium, Available online: https:\/\/www.atsdr.cdc.gov\/toxprofiles\/tp.asp?id=48&tid=15."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1007\/s00018-002-8454-2","article-title":"Metallothionein: The multipurpose protein","volume":"59","author":"Coyle","year":"2002","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_6","unstructured":"Sigel, A., Sigel, H., and Sigel, R.K.O. (2009). Metallothioneins and Related Chelators, RSC Publishing. Metal Ions in Life Sciences."},{"key":"ref_7","first-page":"141","article-title":"In vitro and in vivo studies on the degradation of metallothionein","volume":"102","author":"Klaassen","year":"1994","journal-title":"Environ. Health Perspect."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.cdp.2006.12.001","article-title":"Blood cadmium may be associated with bladder carcinogenesis: The Belgian case-control study on bladder cancer","volume":"31","author":"Kellen","year":"2007","journal-title":"Cancer Detect. Prev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.aca.2008.10.035","article-title":"Elevated metallothionein-bound cadmium concentrations in urine from bladder carcinoma patients, investigated by size exclusion chromatography-inductively coupled plasma mass spectrometry","volume":"631","author":"Wolf","year":"2009","journal-title":"Anal. Chim. Acta"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7204","DOI":"10.1007\/s11356-013-1716-8","article-title":"Cadmium in blood of Tunisian men and risk of bladder cancer: Interactions with arsenic exposure and smoking","volume":"20","author":"Olmedo","year":"2013","journal-title":"Environ. Sci. Pollut. Res. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1111\/iju.13024","article-title":"Association between levels of urinary heavy metals and increased risk of urothelial carcinoma","volume":"23","author":"Chang","year":"2016","journal-title":"Int. J. Urol."},{"key":"ref_12","first-page":"455","article-title":"Cadmium-induced Malignant Transformation of Human Prostate Epithelial Cells","volume":"61","author":"Achanzar","year":"2001","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/S0014-4827(03)00062-4","article-title":"Effects of cadmium on DNA-(Cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation","volume":"286","author":"Takiguchi","year":"2003","journal-title":"Exp. Cell Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/S0895-3988(08)60051-3","article-title":"Malignant transformation and abnormal expression of eukaryotic initiation factor in bronchial epithelial cells induced by cadmium chloride","volume":"21","author":"Lei","year":"2008","journal-title":"Biomed. Environ. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1093\/toxsci\/kfh086","article-title":"Inorganic Cadmium- and Arsenite-Induced Malignant Transformation of Human Bladder Urothelial Cells","volume":"79","author":"Sens","year":"2004","journal-title":"Toxicol. Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s00709-010-0112-1","article-title":"Formation and maintenance of blood\u2013urine barrier in urothelium","volume":"246","author":"Kreft","year":"2010","journal-title":"Protoplasma"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1177\/019262339502300202","article-title":"An Introduction to Drug Disposition: The Basic Principles of Absorption, Distribution, Metabolism, and Excretion","volume":"23","author":"Caldwell","year":"1995","journal-title":"Toxicol. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"112","DOI":"10.3390\/cells4020112","article-title":"Signaling during Kidney Development","volume":"4","author":"Krause","year":"2015","journal-title":"Cells"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4813","DOI":"10.1021\/ja01574a064","article-title":"A Cadmium Protein from Equine Kidney Cortex","volume":"79","author":"Margoshes","year":"1957","journal-title":"J. Am. Chem. Soc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"8509","DOI":"10.1021\/bi00423a001","article-title":"Biochemistry of metallothionein","volume":"27","year":"1988","journal-title":"Biochemistry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1289\/ehp.8454135","article-title":"NMR analysis of the structure and metal sequestering properties of metallothioneins","volume":"54","author":"Hunt","year":"1984","journal-title":"Environ. Health Perspect."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.ccr.2011.07.006","article-title":"State-of-the-art of metallothioneins at the beginning of the 21st century","volume":"256","author":"Capdevila","year":"2012","journal-title":"Coord. Chem. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1093\/jn\/126.4.825","article-title":"Transgenic mice that overexpress metallothionein-I resist dietary zinc deficiency","volume":"126","author":"Dalton","year":"1996","journal-title":"J. Nutr."},{"key":"ref_24","first-page":"1782","article-title":"Metallothionein I and II protect against zinc deficiency and zinc toxicity in mice","volume":"126","author":"Kelly","year":"1996","journal-title":"J. Nutr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1093\/jn\/133.1.45","article-title":"Pancreatic metallothionein-I may play a role in zinc homeostasis during maternal dietary zinc deficiency in mice","volume":"133","author":"Lee","year":"2003","journal-title":"J. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1002\/jnr.21043","article-title":"Novel roles for metallothionein-I + II (MT-I + II) in defense responses, neurogenesis, and tissue restoration after traumatic brain injury: Insights from global gene expression profiling in wild-type and MT-I + II knockout mice","volume":"84","author":"Penkowa","year":"2006","journal-title":"J. Neurosci. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5506","DOI":"10.1074\/jbc.270.10.5506","article-title":"Enhanced sensitivity to oxidative stress in cultured embryonic cells from transgenic mice deficient in metallothionein I and II genes","volume":"270","author":"Lazo","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/308513a0","article-title":"Characterization of DNA sequences through which cadmium and glucocorticoid hormones induce human metallothionein-IIA gene","volume":"308","author":"Karin","year":"1984","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1159\/000365550","article-title":"Expression, regulation and function of human metallothioneins in endothelial cells","volume":"51","author":"Schulkens","year":"2014","journal-title":"J. Vasc. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1002\/path.2489","article-title":"Over-expression of metallothionein predicts chemoresistance in breast cancer","volume":"217","author":"Yap","year":"2009","journal-title":"J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.mce.2008.12.017","article-title":"Expression of functional metallothionein isoforms in papillary thyroid cancer","volume":"302","author":"Liu","year":"2009","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_32","first-page":"1757","article-title":"Localization of metallothionein in urothelial carcinoma of the human urinary bladder: An immunohistochemical study including correlation with HLA-DR antigen, p53, and proliferation indices","volume":"21","author":"Ioachim","year":"2001","journal-title":"Anticancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/carcin\/23.1.81","article-title":"Metallothionein 2A expression is associated with cell proliferation in breast cancer","volume":"23","author":"Jin","year":"2002","journal-title":"Carcinogenesis"},{"key":"ref_34","first-page":"26","article-title":"Structure, organization, and regulation of human metallothionein IF gene: Differential and cell-type-specific expression in response to heavy metals and glucocorticoids","volume":"6","author":"Varshney","year":"1986","journal-title":"Mol. Cell. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.etap.2012.08.002","article-title":"Expression of metallothionein isoforms in peripheral blood leukocytes from Thai population residing in cadmium-contaminated areas","volume":"34","author":"Boonprasert","year":"2012","journal-title":"Environ. Toxicol. Pharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"G877","DOI":"10.1152\/ajpgi.00251.2007","article-title":"Metallothionein is a crucial protective factor against Helicobacter pylori-induced gastric erosive lesions in a mouse model","volume":"294","author":"Mita","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_37","first-page":"25","article-title":"Chemistry and biochemistry of metallothionein","volume":"52","author":"Kojima","year":"1987","journal-title":"Exp. Suppl."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1039\/C5MT00225G","article-title":"Defining the metal binding pathways of human metallothionein 1a: Balancing zinc availability and cadmium seclusion","volume":"8","author":"Irvine","year":"2016","journal-title":"Metallomics"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Kimura, T., and Kambe, T. (2016). The Functions of Metallothionein and ZIP and ZnT Transporters: An Overview and Perspective. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17030336"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1080\/10409230091169168","article-title":"Induction, Regulation, Degradation, and Biological Significance of Mammalian Metallothioneins","volume":"35","author":"Miles","year":"2000","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1074\/mcp.M113.033373","article-title":"Quantitation of Human Metallothionein Isoforms: A Family of Small, Highly Conserved, Cysteine-rich Proteins","volume":"13","author":"Mehus","year":"2014","journal-title":"Mol. Cell. Proteom."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"C1461","DOI":"10.1152\/ajpcell.00570.2009","article-title":"Endothelial metallothionein expression and intracellular free zinc levels are regulated by shear stress","volume":"299","author":"Conway","year":"2010","journal-title":"Am. J. Physiol. Cell. Physiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6506","DOI":"10.1016\/S0021-9258(19)39356-1","article-title":"Cell-type specific and differential regulation of the human metallothionein genes. Correlation with DNA methylation and chromatin structure","volume":"265","author":"Jahroudi","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1248\/yakushi.127.665","article-title":"Heavy metal responses of the human metallothionein isoform genes","volume":"127","author":"Miura","year":"2007","journal-title":"J. Pharm. Soc. Jpn."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/0092-8674(84)90322-2","article-title":"Structural and functional analysis of the human metallothionein-IA gene: Differential induction by metal ions and glucocorticoids","volume":"37","author":"Richards","year":"1984","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1101\/gad.1301805","article-title":"Metal-responsive transcription factor (MTF-1) handles both extremes, copper load and copper starvation, by activating different genes","volume":"19","author":"Selvaraj","year":"2005","journal-title":"Genes Dev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"16516","DOI":"10.1073\/pnas.1207737109","article-title":"Single nucleotide in the MTF-1 binding site can determine metal-specific transcription activation","volume":"109","author":"Sims","year":"2012","journal-title":"PNAS"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1016\/S0021-9258(18)69121-5","article-title":"Regulation of human metallothionein (MT) genes. Differential expression of MTI-F, MTI-G, and MTII-A genes in the hepatoblastoma cell line (HepG2)","volume":"263","author":"Sadhu","year":"1988","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/0041-008X(88)90221-9","article-title":"Mechanisms of regulation of rat hepatic metallothionein-I and metallothionein-II levels following administration of zinc","volume":"92","author":"Andrews","year":"1988","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/BF02917244","article-title":"Regulation of the isoforms of metallothionein","volume":"21","author":"Klaassen","year":"1989","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1016\/j.chemosphere.2007.11.067","article-title":"Cloning of a river pufferfish (Takifugu obscurus) metallothionein cDNA and study of its induction profile in cadmium-exposed fish","volume":"71","author":"Kim","year":"2008","journal-title":"Chemosphere"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1046\/j.1365-2559.1997.2140848.x","article-title":"Significance of metallothionein overexpression in human tumours","volume":"31","author":"Jasani","year":"1997","journal-title":"Histopathology"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Chaney, R.L. (2010). Cadmium and Zinc. Trace Elements in Soils, Wiley.","DOI":"10.1002\/9781444319477.ch17"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1002\/bip.21680","article-title":"Zinc to cadmium replacement in the A. thaliana SUPERMAN Cys\u2082 His\u2082 zinc finger induces structural rearrangements of typical DNA base determinant positions","volume":"95","author":"Malgieri","year":"2011","journal-title":"Biopolymers"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1039\/C4MT00080C","article-title":"Cadmium\u2013zinc exchange and their binary relationship in the structure of Zn-related proteins: A mini review","volume":"6","author":"Tang","year":"2014","journal-title":"Metallomics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.mam.2012.05.011","article-title":"The SLC39 family of zinc transporters","volume":"34","author":"Jeong","year":"2013","journal-title":"Mol. Asp. Med."},{"key":"ref_57","first-page":"583","article-title":"Normal human urothelial cells in vitro: Proliferation and induction of stratification","volume":"71","author":"Southgate","year":"1994","journal-title":"Lab. Investig."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"F459","DOI":"10.1152\/ajprenal.00040.2005","article-title":"A biomimetic tissue from cultured normal human urothelial cells: Analysis of physiological function","volume":"289","author":"Cross","year":"2005","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1016\/j.freeradbiomed.2004.03.010","article-title":"Cadmium inhibits the electron transfer chain and induces reactive oxygen species","volume":"36","author":"Wang","year":"2004","journal-title":"Free Radic. Biol. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1111\/j.1469-8137.2008.02512.x","article-title":"Origin of cadmium-induced reactive oxygen species production: Mitochondrial electron transfer versus plasma membrane NADPH oxidase","volume":"179","author":"Heyno","year":"2008","journal-title":"New Phytol."},{"key":"ref_61","first-page":"484","article-title":"Induction of metallothionein-I mRNA in cultured cells by heavy metals and iodoacetate: Evidence for gratuitous inducers","volume":"4","author":"Durnam","year":"1984","journal-title":"Mol. Cell. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"16379","DOI":"10.1016\/S0021-9258(18)42013-3","article-title":"Heme-hemopexin-mediated induction of metallothionein gene expression","volume":"267","author":"Alam","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1042\/BJ20051143","article-title":"Metallothionein protects against oxidative stress-induced lysosomal destabilization","volume":"394","author":"Baird","year":"2006","journal-title":"Biochem. J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1073\/pnas.91.4.1219","article-title":"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","volume":"91","author":"Palmiter","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","first-page":"9","article-title":"Differential Gene-Expression of Metallothionein 1M and 1G in Response to Zinc in Sertoli TM4 Cells","volume":"14","author":"Kheradmand","year":"2010","journal-title":"Iran Biomed. J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1007\/s12263-015-0494-y","article-title":"Zinc-induced upregulation of metallothionein (MT)-2A is predicted by gene expression of zinc transporters in healthy adults","volume":"10","author":"Chu","year":"2015","journal-title":"Genes Nutr."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"22413","DOI":"10.1074\/jbc.M114.548677","article-title":"Heavy metal-induced metallothionein expression is regulated by specific protein phosphatase 2A complexes","volume":"289","author":"Chen","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2870","DOI":"10.1002\/j.1460-2075.1994.tb06581.x","article-title":"The transcription factor MTF-1 is essential for basal and heavy metal-induced metallothionein gene expression","volume":"13","author":"Heuchel","year":"1994","journal-title":"EMBO J."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1093\/toxsci\/kfj174","article-title":"Metallothionein-1 and -2 Expression in Cadmium- or Arsenic-Derived Human Malignant Urothelial Cells and Tumor Heterotransplants and as a Prognostic Indicator in Human Bladder Cancer","volume":"91","author":"Zhou","year":"2006","journal-title":"Toxicol. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.bbrc.2013.10.044","article-title":"Topographical analysis of As-induced folding of \u03b1-MT1a","volume":"441","author":"Irvine","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"4841","DOI":"10.1073\/pnas.95.9.4841","article-title":"Regulation of the zinc transporter ZnT-1 by dietary zinc","volume":"95","author":"McMahon","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/S0014-5793(97)00082-3","article-title":"Human metallothionein gene MT1L mRNA is present in several human tissues but is unlikely to produce a metallothionein protein","volume":"404","author":"Holloway","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s00439-005-0125-6","article-title":"Human-specific nonsense mutations identified by genome sequence comparisons","volume":"119","author":"Hahn","year":"2006","journal-title":"Hum. Genet."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1089\/ars.2005.7.80","article-title":"Heme oxygenase-1: Redox regulation of a stress protein in lung and cell culture models","volume":"7","author":"Ryter","year":"2005","journal-title":"Antioxid. Redox Signal."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.tox.2010.11.017","article-title":"Induction of apoptosis in human leukemia cells through the production of reactive oxygen species and activation of HMOX1 and Noxa by benzene, toluene, and o-xylene","volume":"280","author":"Sarma","year":"2011","journal-title":"Toxicology"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/S0887-2333(97)00045-3","article-title":"Effect of cadmium on active ion transport and cytotoxicity in cultured renal epithelial cells (A6)","volume":"11","author":"Faurskov","year":"1997","journal-title":"Toxicol. In Vitro"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s12931-015-0191-9","article-title":"Tight junction disruption by cadmium in an in vitro human airway tissue model","volume":"16","author":"Cao","year":"2015","journal-title":"Respir. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"993","DOI":"10.3748\/wjg.v13.i7.993","article-title":"Metallothionein: An overview","volume":"13","author":"Thirumoorthy","year":"2007","journal-title":"World J. Gastroenterol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1039\/C3MT00132F","article-title":"Metallothionein polymorphisms in pathological processes","volume":"6","author":"Raudenska","year":"2013","journal-title":"Metallomics"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"6333","DOI":"10.1073\/pnas.89.14.6333","article-title":"MT-III, a brain-specific member of the metallothionein gene family","volume":"89","author":"Palmiter","year":"1992","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1289\/ehp.00108413","article-title":"Metallothionein isoform 3 as a potential biomarker for human bladder cancer","volume":"108","author":"Sens","year":"2000","journal-title":"Environ. Health Perspect."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1093\/toxsci\/kfl065","article-title":"Enhanced expression of metallothionein isoform 3 protein in tumor heterotransplants derived from As+3- and Cd+2-transformed human urothelial cells","volume":"93","author":"Zhou","year":"2006","journal-title":"Toxicol. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/1475-2867-11-2","article-title":"Differences in the epigenetic regulation of MT-3 gene expression between parental and Cd+2 or As+3 transformed human urothelial cells","volume":"11","author":"Somji","year":"2011","journal-title":"Cancer Cell Int."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1111\/his.12660","article-title":"Metallothionein gene expression is altered in oral cancer and may predict metastasis and patient outcomes","volume":"67","author":"Rodriguez","year":"2015","journal-title":"Histopathology"},{"key":"ref_85","unstructured":"(1993). International Agency for Research on Cancer Beryllium, cadmium, mercury, and exposures in the glass manufacturing industry. IARC Monographs on the Evaluation of the Carcinogenic Risks to Humans, IARC."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1093\/carcin\/20.9.1819","article-title":"Nickel-induced transformation shifts the balance between HIF-1 and p53 transcription factors","volume":"20","author":"Salnikow","year":"1999","journal-title":"Carcinogenesis"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1416","DOI":"10.1016\/j.bbamcr.2012.01.005","article-title":"The taste of heavy metals: Gene regulation by MTF-1","volume":"1823","author":"Lindert","year":"2012","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Res."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1248\/jhs.55.484","article-title":"Mechanisms of Heavy Metal Sensing by Metal Response Element-binding Transcription Factor-1","volume":"55","author":"Kimura","year":"2009","journal-title":"J. Health Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1248\/jhs.47.513","article-title":"Molecular Mechanism of the Metallothionein Gene Expression Mediated by Metal-Responsive Transcription Factor 1","volume":"47","author":"Otsuka","year":"2001","journal-title":"J. Health Sci."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"34803","DOI":"10.1074\/jbc.M007339200","article-title":"The transcription factor MTF-1 mediates metal regulation of the mouse ZnT1 gene","volume":"275","author":"Langmade","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2818","DOI":"10.1073\/pnas.0914941107","article-title":"STAT5-glucocorticoid receptor interaction and MTF-1 regulate the expression of ZnT2 (Slc30a2) in pancreatic acinar cells","volume":"107","author":"Guo","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"17029","DOI":"10.1038\/sigtrans.2017.29","article-title":"The emerging role of zinc transporters in cellular homeostasis and cancer","volume":"2","author":"Bafaro","year":"2017","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.tiv.2009.11.003","article-title":"Regulation of metallothioneins and ZnT-1 transporter expression in human hepatoma cells HepG2 exposed to zinc and cadmium","volume":"24","author":"Urani","year":"2010","journal-title":"Toxicol. In Vitro"},{"key":"ref_94","first-page":"e949514","article-title":"Impact of Cadmium on Intracellular Zinc Levels in HepG2 Cells: Quantitative Evaluations and Molecular Effects, Impact of Cadmium on Intracellular Zinc Levels in HepG2 Cells: Quantitative Evaluations and Molecular Effects","volume":"2015","author":"Urani","year":"2015","journal-title":"BioMed Res. Int. BioMed Res. Int."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.proghi.2008.10.001","article-title":"The role of metallothionein in oncogenesis and cancer prognosis","volume":"44","author":"Pedersen","year":"2009","journal-title":"Prog. Histochem. Cytochem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0300-483X(00)00436-4","article-title":"Cadmium adaptation in the lung\u2014A double-edged sword?","volume":"160","author":"Hart","year":"2001","journal-title":"Toxicology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/S0300-483X(00)00215-8","article-title":"Suppressed oxidant-induced apoptosis in cadmium adapted alveolar epithelial cells and its potential involvement in cadmium carcinogenesis","volume":"147","author":"Eneman","year":"2000","journal-title":"Toxicology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/S0300-483X(00)00419-4","article-title":"Inhibition of oxidative DNA repair in cadmium-adapted alveolar epithelial cells and the potential involvement of metallothionein","volume":"161","author":"Potts","year":"2001","journal-title":"Toxicology"},{"key":"ref_99","first-page":"1829","article-title":"Modulation of Both Cisplatin Nephrotoxicity and Drug Resistance in Murine Bladder Tumor by Controlling Metallothionein Synthesis","volume":"53","author":"Satoh","year":"1993","journal-title":"Cancer Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s00345-006-0141-8","article-title":"Metallothionein in bladder cancer: Correlation of overexpression with poor outcome after chemotherapy","volume":"25","author":"Eltze","year":"2007","journal-title":"World J. Urol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/j.urology.2005.09.033","article-title":"Metallothionein expression as prognostic factor for transitional cell carcinoma of bladder","volume":"67","author":"Yamasaki","year":"2006","journal-title":"Urology"},{"key":"ref_102","doi-asserted-by":"crossref","unstructured":"Southgate, J., Masters, J.R.W., and Trejdosiewicz, L.K. (2002). Culture of Human Urothelium. Culture of Epithelial Cells, John Wiley & Sons, Inc.","DOI":"10.1002\/0471221201.ch12"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1007\/978-1-61779-191-8_14","article-title":"Permeability of differentiated human urothelium in vitro","volume":"763","author":"Rubenwolf","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1038\/cdd.2017.10","article-title":"Heterarchy of transcription factors driving basal and luminal cell phenotypes in human urothelium","volume":"24","author":"Fishwick","year":"2017","journal-title":"Cell Death Differ."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nbt.3519","article-title":"Near-optimal probabilistic RNA-seq quantification","volume":"34","author":"Bray","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.12688\/f1000research.7563.1","article-title":"Differential analyses for RNA-seq: Transcript-level estimates improve gene-level inferences","volume":"4","author":"Soneson","year":"2015","journal-title":"F1000Research"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1038\/nmeth.4324","article-title":"Differential analysis of RNA-seq incorporating quantification uncertainty","volume":"14","author":"Pimentel","year":"2017","journal-title":"Nat. Methods"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1016\/S0002-9440(10)65709-4","article-title":"Uroplakin gene expression by normal and neoplastic human urothelium","volume":"153","author":"Lobban","year":"1998","journal-title":"Am. J. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/6\/1344\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:38:28Z","timestamp":1760186308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/6\/1344"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,17]]},"references-count":108,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,3]]}},"alternative-id":["ijms20061344"],"URL":"https:\/\/doi.org\/10.3390\/ijms20061344","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,17]]}}}