{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T04:56:25Z","timestamp":1774328185994,"version":"3.50.1"},"reference-count":115,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,23]],"date-time":"2023-12-23T00:00:00Z","timestamp":1703289600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Environmental Health Sciences","award":["R01ES016893"],"award-info":[{"award-number":["R01ES016893"]}]},{"name":"National Institute of Environmental Health Sciences","award":["R35ES03287"],"award-info":[{"award-number":["R35ES03287"]}]},{"name":"National Institute of Environmental Health Sciences","award":["T32ES011564"],"award-info":[{"award-number":["T32ES011564"]}]},{"name":"Jewish Heritage Foundation for Excellence","award":["R01ES016893"],"award-info":[{"award-number":["R01ES016893"]}]},{"name":"Jewish Heritage Foundation for Excellence","award":["R35ES03287"],"award-info":[{"award-number":["R35ES03287"]}]},{"name":"Jewish Heritage Foundation for Excellence","award":["T32ES011564"],"award-info":[{"award-number":["T32ES011564"]}]},{"name":"University of Louisville Graduate School Dissertation Completion Award","award":["R01ES016893"],"award-info":[{"award-number":["R01ES016893"]}]},{"name":"University of Louisville Graduate School Dissertation Completion Award","award":["R35ES03287"],"award-info":[{"award-number":["R35ES03287"]}]},{"name":"University of Louisville Graduate School Dissertation Completion Award","award":["T32ES011564"],"award-info":[{"award-number":["T32ES011564"]}]},{"name":"University of Louisville","award":["R01ES016893"],"award-info":[{"award-number":["R01ES016893"]}]},{"name":"University of Louisville","award":["R35ES03287"],"award-info":[{"award-number":["R35ES03287"]}]},{"name":"University of Louisville","award":["T32ES011564"],"award-info":[{"award-number":["T32ES011564"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Hexavalent chromium [Cr(VI)] is a known human lung carcinogen with widespread exposure in environmental and occupational settings. Despite well-known cancer risks, the molecular mechanisms of Cr(VI)-induced carcinogenesis are not well understood, but a major driver of Cr(VI) carcinogenesis is chromosome instability. Previously, we reported Cr(VI) induced numerical chromosome instability, premature centriole disengagement, centrosome amplification, premature centromere division, and spindle assembly checkpoint bypass. A key regulator of these events is securin, which acts by regulating the cleavage ability of separase. Thus, in this study we investigated securin disruption by Cr(VI) exposure. We exposed human lung cells to a particulate Cr(VI) compound, zinc chromate, for acute (24 h) and prolonged (120 h) time points. We found prolonged Cr(VI) exposure caused marked decrease in securin levels and function. After prolonged exposure at the highest concentration, securin protein levels were decreased to 15.3% of control cells, while securin mRNA quantification was 7.9% relative to control cells. Additionally, loss of securin function led to increased separase activity manifested as enhanced cleavage of separase substrates; separase, kendrin, and SCC1. These data show securin is targeted by prolonged Cr(VI) exposure in human lung cells. Thus, a new mechanistic model for Cr(VI)-induced carcinogenesis emerges with centrosome and centromere disruption as key components of numerical chromosome instability, a key driver in Cr(VI) carcinogenesis.<\/jats:p>","DOI":"10.3390\/ijms25010256","type":"journal-article","created":{"date-parts":[[2023,12,24]],"date-time":"2023-12-24T20:44:15Z","timestamp":1703450655000},"page":"256","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Hexavalent Chromium Targets Securin to Drive Numerical Chromosome Instability in Human Lung Cells"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2974-7605","authenticated-orcid":false,"given":"Jennifer H.","family":"Toyoda","sequence":"first","affiliation":[{"name":"Wise Laboratory for Environmental and Genetic Toxicology, University of Louisville, 500 S Preston Street, Building 55A, Room 1422, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julieta","family":"Martino","sequence":"additional","affiliation":[{"name":"Wise Laboratory for Environmental and Genetic Toxicology, University of Louisville, 500 S Preston Street, Building 55A, Room 1422, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel M.","family":"Speer","sequence":"additional","affiliation":[{"name":"Wise Laboratory for Environmental and Genetic Toxicology, University of Louisville, 500 S Preston Street, Building 55A, Room 1422, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5292-0843","authenticated-orcid":false,"given":"Idoia","family":"Meaza","sequence":"additional","affiliation":[{"name":"Wise Laboratory for Environmental and Genetic Toxicology, University of Louisville, 500 S Preston Street, Building 55A, Room 1422, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6711-0314","authenticated-orcid":false,"given":"Haiyan","family":"Lu","sequence":"additional","affiliation":[{"name":"Wise Laboratory for Environmental and Genetic Toxicology, University of Louisville, 500 S Preston Street, Building 55A, Room 1422, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aggie R.","family":"Williams","sequence":"additional","affiliation":[{"name":"Wise Laboratory for Environmental and Genetic Toxicology, University of Louisville, 500 S Preston Street, Building 55A, Room 1422, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia M.","family":"Bolt","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, The University of New Mexico College of Pharmacy, Albuquerque, NM 87131, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph Calvin","family":"Kouokam","sequence":"additional","affiliation":[{"name":"Wise Laboratory for Environmental and Genetic Toxicology, University of Louisville, 500 S Preston Street, Building 55A, Room 1422, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abou El-Makarim","family":"Aboueissa","sequence":"additional","affiliation":[{"name":"Department of Mathematics and Statistics, University of Southern Maine, Portland, ME 04104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2587-2855","authenticated-orcid":false,"suffix":"Sr.","given":"John Pierce","family":"Wise","sequence":"additional","affiliation":[{"name":"Wise Laboratory for Environmental and Genetic Toxicology, University of Louisville, 500 S Preston Street, Building 55A, Room 1422, Louisville, KY 40292, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,23]]},"reference":[{"key":"ref_1","unstructured":"Wilbur, S., Abadin, H., Fay, M., Yu, D., Tencza, B., Ingerman, L., Klotzbach, J., and James, S. (2012). Toxicological Profile for Chromium, Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profiles; Agency for Toxic Substances and Disease Registry (US)."},{"key":"ref_2","unstructured":"IARC Working Group on the Evaluation of Carcinogenic Risk to Humans (2012). Arsenic, Metals, Fibres and Dusts, International Agency for Research on Cancer."},{"key":"ref_3","first-page":"81","article-title":"Role of Chemical Species and Exposure Characteristics in Cancer among Persons Occupationally Exposed to Chromium Compounds","volume":"19","author":"Langard","year":"1993","journal-title":"Scand. J. Work. Environ. Health"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1136\/oem.44.4.250","article-title":"A Mortality Study of Nickel\/Chromium Platers","volume":"44","author":"Sorahan","year":"1987","journal-title":"Occup. Environ. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1136\/oem.48.5.299","article-title":"Mortality from Respiratory Cancer and Other Causes in United Kingdom Chromate Production Workers","volume":"48","author":"Davies","year":"1991","journal-title":"Occup. Environ. Med."},{"key":"ref_6","first-page":"3","article-title":"Nasal Toxicity, Carcinogenicity, and Olfactory Uptake of Metals","volume":"31","author":"Sunderman","year":"2001","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"157","DOI":"10.7888\/juoeh.40.157","article-title":"Cancer Risks of Hexavalent Chromium in the Respiratory Tract","volume":"40","author":"Yatera","year":"2018","journal-title":"J. UOEH"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1136\/thx.33.3.372","article-title":"Lung Cancer in Japanese Chromate Workers","volume":"33","author":"Ohsaki","year":"1978","journal-title":"Thorax"},{"key":"ref_9","first-page":"71","article-title":"Occurrence of Lung Cancer in Workers Producing Chromium Pigments","volume":"40","author":"Langard","year":"1983","journal-title":"Br. J. Ind. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1136\/oem.60.6.451","article-title":"Lung Cancer Mortality among Chromate Production Workers","volume":"60","author":"Luippold","year":"2003","journal-title":"Occup. Environ. Med."},{"key":"ref_11","unstructured":"Agency for Toxic Substances and Disease Registry (2012). Toxicological Profile for Chromium, U.S. Department of Health and Human Services, Public Health Service."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7060","DOI":"10.1021\/es060061i","article-title":"The Contemporary Anthropogenic Chromium Cycle","volume":"40","author":"Johnson","year":"2006","journal-title":"Environ. Sci. Technol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1080\/00984100290071018","article-title":"Is Hexavalent Chromium Carcinogenic via Ingestion? A Weight-of-Evidence Review","volume":"65","author":"Proctor","year":"2002","journal-title":"J. Toxicol. Environ. Health A"},{"key":"ref_14","first-page":"1-G4","article-title":"NTP Toxicity Studies of Sodium Dichromate Dihydrate (CAS No. 7789-12-0) Administered in Drinking Water to Male and Female F344\/N Rats and B6C3F1 Mice and Male BALB\/c and Am3-C57BL\/6 Mice","volume":"72","author":"Bucher","year":"2007","journal-title":"Toxic Rep. Ser."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/1476-069X-10-50","article-title":"Oral Ingestion of Hexavalent Chromium through Drinking Water and Cancer Mortality in an Industrial Area of Greece\u2014an Ecological Study","volume":"10","author":"Linos","year":"2011","journal-title":"Environ. Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1097\/EDE.0b013e31815cea4c","article-title":"Cancer Mortality in a Chinese Population Exposed to Hexavalent Chromium in Drinking Water","volume":"19","author":"Beaumont","year":"2008","journal-title":"Epidemiology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.mrrev.2007.11.005","article-title":"Lack of Genotoxic Effects in Hematopoietic and Gastrointestinal Cells of Mice Receiving Chromium(VI) with the Drinking Water","volume":"659","author":"Balansky","year":"2008","journal-title":"Mutat. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"431","DOI":"10.3109\/10408449709078442","article-title":"Toxicity and Carcinogenicity of Cr(VI) in Animal Models and Humans","volume":"27","author":"Costa","year":"1997","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S1726-4901(09)70059-0","article-title":"Acute Severe Chromium Poisoning after Dermal Exposure to Hexavalent Chromium","volume":"72","author":"Lin","year":"2009","journal-title":"J. Chin. Med. Assoc."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1080\/15287390306388","article-title":"Human Health Risk and Exposure Assessment of Chromium (VI) in Tap Water","volume":"66","author":"Paustenbach","year":"2003","journal-title":"J. Toxicol. Environ. Health A"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1007\/s00420-004-0560-z","article-title":"Monitoring of Chromium and Nickel in Biological Fluids of Stainless Steel Welders Using the Flux-Cored-Wire (FCW) Welding Method","volume":"77","author":"Stridsklev","year":"2004","journal-title":"Int. Arch. Occup. Environ. Health"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1177\/096032719301200506","article-title":"Monitoring of Total Chromium in Rat Fluids and Lymphocytes Following Intratracheal Administration of Soluble Trivalent or Hexavalent Chromium Compounds","volume":"12","author":"Gao","year":"1993","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1038\/jes.2016.85","article-title":"Biomarkers of Oxidative Stress in Electroplating Workers Exposed to Hexavalent Chromium","volume":"28","author":"Pan","year":"2018","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1385\/BTER:74:1:41","article-title":"Rats Retain Chromium in Tissues Following Chronic Ingestion of Drinking Water Containing Hexavalent Chromium","volume":"74","author":"Sutherland","year":"2000","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/j.1600-0773.1978.tb02182.x","article-title":"Whole Blood Chromium Level and Chromium Excretion in the Rat after Zinc Chromate Inhalation","volume":"42","author":"Langard","year":"1978","journal-title":"Acta Pharmacol. Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"24","DOI":"10.3389\/fonc.2019.00024","article-title":"The Effect of Hexavalent Chromium on the Incidence and Mortality of Human Cancers: A Meta-Analysis Based on Published Epidemiological Cohort Studies","volume":"9","author":"Deng","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1006\/bbrc.1997.7425","article-title":"Mutations of the P53 Gene in Human Lung Cancer from Chromate-Exposed Workers","volume":"239","author":"Kondo","year":"1997","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1002\/mc.10035","article-title":"Frequent Microsatellite Instability in Lung Cancer from Chromate-Exposed Workers","volume":"33","author":"Hirose","year":"2002","journal-title":"Mol. Carcinog."},{"key":"ref_29","first-page":"353","article-title":"Carcinogenicity of Hexavalent Chromium","volume":"128","author":"Holmes","year":"2008","journal-title":"Indian. J. Med. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1042\/BST0381650","article-title":"Aneuploidy as an Early Mechanistic Event in Metal Carcinogenesis","volume":"38","author":"Wise","year":"2010","journal-title":"Biochem. Soc. Trans."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.tox.2014.08.009","article-title":"Assessment of the Mode of Action for Hexavalent Chromium-Induced Lung Cancer Following Inhalation Exposures","volume":"325","author":"Proctor","year":"2014","journal-title":"Toxicology"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4041","DOI":"10.1158\/0008-5472.CAN-05-3312","article-title":"Chronic Exposure to Lead Chromate Causes Centrosome Abnormalities and Aneuploidy in Human Lung Cells","volume":"66","author":"Holmes","year":"2006","journal-title":"Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1021\/tx900360w","article-title":"Chronic Exposure to Zinc Chromate Induces Centrosome Amplification and Spindle Assembly Checkpoint Bypass in Human Lung Fibroblasts","volume":"23","author":"Holmes","year":"2010","journal-title":"Chem. Res. Toxicol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4203","DOI":"10.1158\/0008-5472.CAN-18-0531","article-title":"Hexavalent Chromium-Induced Chromosome Instability Drives Permanent and Heritable Numerical and Structural Changes and a DNA Repair-Deficient Phenotype","volume":"78","author":"Wise","year":"2018","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1093\/toxsci\/kfj070","article-title":"Depletion of Securin Increases Arsenite-Induced Chromosome Instability and Apoptosis via a P53-Independent Pathway","volume":"90","author":"Chao","year":"2006","journal-title":"Toxicol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/S0092-8674(01)00340-3","article-title":"Securin Is Required for Chromosomal Stability in Human Cells","volume":"105","author":"Jallepalli","year":"2001","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1126\/science.285.5426.418","article-title":"Identification of a Vertebrate Sister-Chromatid Separation Inhibitor Involved in Transformation and Tumorigenesis","volume":"285","author":"Zou","year":"1999","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3866","DOI":"10.1091\/mbc.e10-02-0124","article-title":"A Centrosome-Autonomous Signal That Involves Centriole Disengagement Permits Centrosome Duplication in G2 Phase after DNA Damage","volume":"21","author":"Inanc","year":"2010","journal-title":"Mol. Biol. Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.ceb.2005.12.008","article-title":"Controlling Centrosome Number: Licenses and Blocks","volume":"18","author":"Tsou","year":"2006","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1038\/nature04985","article-title":"Mechanism Limiting Centrosome Duplication to Once per Cell Cycle","volume":"442","author":"Tsou","year":"2006","journal-title":"Nature"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Agircan, F.G., Schiebel, E., and Mardin, B.R. (2014). Separate to Operate: Control of Centrosome Positioning and Separation. Philos. Trans. R. Soc. Lond. B Biol. Sci., 369.","DOI":"10.1098\/rstb.2013.0461"},{"key":"ref_42","first-page":"5386","article-title":"A Yeast Gene Essential for Regulation of Spindle Pole Duplication","volume":"8","author":"Baum","year":"1988","journal-title":"Mol. Cell. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.canlet.2004.12.028","article-title":"Centrosome Amplification, Chromosome Instability and Cancer Development","volume":"230","author":"Fukasawa","year":"2005","journal-title":"Cancer Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"43","DOI":"10.20517\/2394-4722.2018.24","article-title":"Centrosome Aberrations and Chromosome Instability Contribute to Tumorigenesis and Intra-Tumor Heterogeneity","volume":"4","author":"Jusino","year":"2018","journal-title":"J. Cancer Metastasis Treat."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.ceb.2003.11.006","article-title":"The Good, the Bad and the Ugly: The Practical Consequences of Centrosome Amplification","volume":"16","author":"Sluder","year":"2004","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1083\/jcb.133.1.99","article-title":"Pds1p, an Inhibitor of Anaphase in Budding Yeast, Plays a Critical Role in the APC and Checkpoint Pathway(s)","volume":"133","author":"Yamamoto","year":"1996","journal-title":"J. Cell Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.1101\/gad.10.24.3081","article-title":"Anaphase Initiation in Saccharomyces Cerevisiae Is Controlled by the APC-Dependent Degradation of the Anaphase Inhibitor Pds1p","volume":"10","author":"Peters","year":"1996","journal-title":"Genes Dev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"6617","DOI":"10.1002\/j.1460-2075.1996.tb01052.x","article-title":"Fission Yeast Cut1 and Cut2 Are Essential for Sister Chromatid Separation, Concentrate along the Metaphase Spindle and Form Large Complexes","volume":"15","author":"Funabiki","year":"1996","journal-title":"EMBO J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1016\/S0960-9822(02)01073-4","article-title":"Regulation of Human Separase by Securin Binding and Autocleavage","volume":"12","author":"Waizenegger","year":"2002","journal-title":"Curr. Biol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1093\/toxsci\/kfv146","article-title":"Chronic Exposure to Particulate Chromate Induces Premature Centrosome Separation and Centriole Disengagement in Human Lung Cells","volume":"147","author":"Martino","year":"2015","journal-title":"Toxicol. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1492","DOI":"10.1021\/tx0601410","article-title":"Chronic Exposure to Particulate Chromate Induces Spindle Assembly Checkpoint Bypass in Human Lung Cells","volume":"19","author":"Wise","year":"2006","journal-title":"Chem. Res. Toxicol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1074\/jbc.M203793200","article-title":"DNA Damage-Induced Inhibition of Securin Expression Is Mediated by P53","volume":"278","author":"Zhou","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1016\/S0378-1119(99)00446-1","article-title":"Molecular Cloning, Genomic Organization, and Identification of the Promoter for the Human Pituitary Tumor Transforming Gene (PTTG)","volume":"240","author":"Kakar","year":"1999","journal-title":"Gene"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"8002","DOI":"10.1074\/jbc.M114.615310","article-title":"Positive and Negative Regulation of Vertebrate Separase by Cdk1-Cyclin B1 May Explain Why Securin Is Dispensable","volume":"290","author":"Hellmuth","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/S1534-5807(01)00112-5","article-title":"Regulating Sister Chromatid Separation by Separase Phosphorylation","volume":"2","author":"Nagao","year":"2002","journal-title":"Dev. Cell"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1016\/S0092-8674(01)00603-1","article-title":"Dual Inhibition of Sister Chromatid Separation at Metaphase","volume":"107","author":"Stemmann","year":"2001","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0092-8674(00)00132-X","article-title":"Two Distinct Pathways Remove Mammalian Cohesin from Chromosome Arms in Prophase and from Centromeres in Anaphase","volume":"103","author":"Waizenegger","year":"2000","journal-title":"Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.bbrc.2010.06.063","article-title":"Involvement of a Centrosomal Protein Kendrin in the Maintenance of Centrosome Cohesion by Modulating Nek2A Kinase Activity","volume":"398","author":"Matsuo","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.cub.2012.03.048","article-title":"Kendrin Is a Novel Substrate for Separase Involved in the Licensing of Centriole Duplication","volume":"22","author":"Matsuo","year":"2012","journal-title":"Curr. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/j.cub.2010.05.050","article-title":"Centriole Reduplication during Prolonged Interphase Requires Procentriole Maturation Governed by Plk1","volume":"20","author":"Loncarek","year":"2010","journal-title":"Curr. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.devcel.2009.07.015","article-title":"Polo Kinase and Separase Regulate the Mitotic Licensing of Centriole Duplication in Human Cells","volume":"17","author":"Tsou","year":"2009","journal-title":"Dev. Cell"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/ncb2280","article-title":"Cleavage of Cohesin Rings Coordinates the Separation of Centrioles and Chromatids","volume":"13","author":"Schockel","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Agircan, F.G., and Schiebel, E. (2014). Sensors at Centrosomes Reveal Determinants of Local Separase Activity. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004672"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/S0960-9822(01)00325-6","article-title":"Securin Is Not Required for Cellular Viability, but Is Required for Normal Growth of Mouse Embryonic Fibroblasts","volume":"11","author":"Mei","year":"2001","journal-title":"Curr. Biol."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Pfleghaar, K., Heubes, S., Cox, J., Stemmann, O., and Speicher, M.R. (2005). Securin Is Not Required for Chromosomal Stability in Human Cells. PLoS Biol., 3.","DOI":"10.1371\/journal.pbio.0030416"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.molcel.2005.05.022","article-title":"Mutual Inhibition of Separase and Cdk1 by Two-Step Complex Formation","volume":"19","author":"Gorr","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3325","DOI":"10.1242\/jcs.03083","article-title":"Cyclin-B1-Mediated Inhibition of Excess Separase Is Required for Timely Chromosome Disjunction","volume":"119","author":"Holland","year":"2006","journal-title":"J. Cell Sci."},{"key":"ref_68","first-page":"243","article-title":"Investigation of the Potential Carcinogenicity of a Range of Chromium Containing Materials on Rat Lung","volume":"43","author":"Levy","year":"1986","journal-title":"Br. J. Ind. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.envres.2004.10.001","article-title":"Microscopic Analysis of the Chromium Content in the Chromium-Induced Malignant and Premalignant Bronchial Lesions of the Rat","volume":"99","author":"Takahashi","year":"2005","journal-title":"Environ. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1136\/thx.35.4.294","article-title":"Chromium Content of Lungs of Chromate Workers with Lung Cancer","volume":"35","author":"Tsuneta","year":"1980","journal-title":"Thorax"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S1383-5718(02)00071-2","article-title":"The Cytotoxicity and Genotoxicity of Particulate and Soluble Hexavalent Chromium in Human Lung Cells","volume":"517","author":"Wise","year":"2002","journal-title":"Mutat. Res."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1165\/rcmb.2007-0058OC","article-title":"Neoplastic Transformation of Human Bronchial Cells by Lead Chromate Particles","volume":"37","author":"Xie","year":"2007","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"9","DOI":"10.2486\/indhealth.28.9","article-title":"Synergism of Ascorbic Acid and Glutathione in the Reduction of Hexavalent Chromium In Vitro","volume":"28","author":"Suzuki","year":"1990","journal-title":"Ind. Health"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0048-9697(89)90199-X","article-title":"Molecular Basis of Hexavalent Chromium Carcinogenicity: Effect on Gene Expression","volume":"86","author":"Wetterhahn","year":"1989","journal-title":"Sci. Total Environ."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1007\/BF02917282","article-title":"Mechanism of Chromium(VI) Carcinogenesis. Reactive Intermediates and Effect on Gene Expression","volume":"21","author":"Wetterhahn","year":"1989","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2165","DOI":"10.1093\/carcin\/10.11.2165","article-title":"Chromium Cross-Links Glutathione and Cysteine to DNA","volume":"10","author":"Borges","year":"1989","journal-title":"Carcinogenesis"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1002\/cbic.201900436","article-title":"Molecular Structure of Binary Chromium(III)-DNA Adducts","volume":"21","author":"Brown","year":"2020","journal-title":"Chembiochem"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1795","DOI":"10.1093\/carcin\/14.9.1795","article-title":"Differential Binding of Chromium(VI) and Chromium(III) Complexes to Salmon Sperm Nuclei and Nuclear DNA and Isolated Calf Thymus DNA","volume":"14","author":"Hneihen","year":"1993","journal-title":"Carcinogenesis"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1016\/j.jinorgbio.2007.12.003","article-title":"Isolation of a Novel Chromium(III) Binding Protein from Bovine Liver Tissue after Chromium(VI) Exposure","volume":"102","author":"Peterson","year":"2008","journal-title":"J. Inorg. Biochem."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of Cancer: The next Generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1016\/j.devcel.2016.10.023","article-title":"Living in CIN: Mitotic Infidelity and Its Consequences for Tumor Promotion and Suppression","volume":"39","author":"Funk","year":"2016","journal-title":"Dev. Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1159\/000455804","article-title":"Chromosome Imbalances in Cancer: Molecular Cytogenetics Meets Genomics","volume":"150","author":"Palumbo","year":"2016","journal-title":"Cytogenet. Genome Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nrm2858","article-title":"Genomic Instability--an Evolving Hallmark of Cancer","volume":"11","author":"Negrini","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1021\/tx050033y","article-title":"Guanine-Specific Oxidation of Double-Stranded DNA by Cr(VI) and Ascorbic Acid Forms Spiroiminodihydantoin and 8-Oxo-2\u2032-Deoxyguanosine","volume":"18","author":"Slade","year":"2005","journal-title":"Chem. Res. Toxicol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1016\/j.freeradbiomed.2006.01.028","article-title":"Causes of DNA Single-Strand Breaks during Reduction of Chromate by Glutathione in Vitro and in Cells","volume":"40","author":"Messer","year":"2006","journal-title":"Free Radic. Biol. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1093\/toxsci\/kfw103","article-title":"Prolonged Particulate Hexavalent Chromium Exposure Suppresses Homologous Recombination Repair in Human Lung Cells","volume":"153","author":"Browning","year":"2016","journal-title":"Toxicol. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1093\/carcin\/bgh242","article-title":"Generation of S Phase-Dependent DNA Double-Strand Breaks by Cr(VI) Exposure: Involvement of ATM in Cr(VI) Induction of \u03b3-H2AX","volume":"25","author":"Ha","year":"2004","journal-title":"Carcinogenesis"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"R148","DOI":"10.1016\/j.cub.2014.01.019","article-title":"The Mitotic Origin of Chromosomal Instability","volume":"24","author":"Bakhoum","year":"2014","journal-title":"Curr. Biol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1038\/32688","article-title":"Mutations of Mitotic Checkpoint Genes in Human Cancers","volume":"392","author":"Cahill","year":"1998","journal-title":"Nature"},{"key":"ref_90","first-page":"32","article-title":"Merotelic Kinetochore Orientation, Aneuploidy, and Cancer","volume":"1786","author":"Cimini","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"13692","DOI":"10.1073\/pnas.95.23.13692","article-title":"Genetic Instability of Cancer Cells Is Proportional to Their Degree of Aneuploidy","volume":"95","author":"Duesberg","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/21831","article-title":"Sister-Chromatid Separation at Anaphase Onset Is Promoted by Cleavage of the Cohesin Subunit Scc1","volume":"400","author":"Uhlmann","year":"1999","journal-title":"Nature"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/nature17402","article-title":"Structural Basis of Cohesin Cleavage by Separase","volume":"532","author":"Lin","year":"2016","journal-title":"Nature"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1007\/978-3-030-58971-4_4","article-title":"Structure and Function of the Separase-Securin Complex","volume":"96","author":"Luo","year":"2021","journal-title":"Subcell. Biochem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1083\/jcb.200111001","article-title":"Human Securin Proteolysis Is Controlled by the Spindle Checkpoint and Reveals When the APC\/C Switches from Activation by Cdc20 to Cdh1","volume":"157","author":"Hagting","year":"2002","journal-title":"J. Cell Biol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.sbi.2018.01.012","article-title":"Structural Biology of the Separase-Securin Complex with Crucial Roles in Chromosome Segregation","volume":"49","author":"Luo","year":"2018","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1038\/s41586-021-03764-0","article-title":"Structural Basis of Human Separase Regulation by Securin and CDK1-Cyclin B1","volume":"596","author":"Yu","year":"2021","journal-title":"Nature"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Lou, J., Wang, Y., Yao, C., Jin, L., Wang, X., Xiao, Y., Wu, N., Song, P., Song, Y., and Tan, Y. (2013). Role of DNA Methylation in Cell Cycle Arrest Induced by Cr (VI) in Two Cell Lines. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0071031"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1002\/jat.3793","article-title":"Cr(VI)-Induced Genotoxicity and Cell Cycle Arrest in Human Osteoblast Cell Line MG-63","volume":"39","author":"Monteiro","year":"2019","journal-title":"J. Appl. Toxicol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s11010-012-1423-7","article-title":"Hexavalent Chromium Induces Energy Metabolism Disturbance and P53-Dependent Cell Cycle Arrest via Reactive Oxygen Species in L-02 Hepatocytes","volume":"371","author":"Xiao","year":"2012","journal-title":"Mol. Cell. Biochem."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1007\/s12011-015-0315-6","article-title":"Human Skin Cells Are More Sensitive than Human Lung Cells to the Cytotoxic and Cell Cycle Arresting Impacts of Particulate and Soluble Hexavalent Chromium","volume":"166","author":"Xie","year":"2015","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1002\/(SICI)1098-2744(199907)25:3<219::AID-MC8>3.0.CO;2-X","article-title":"Differential Effects of Arsenic(III) and Chromium(VI) on Nuclear Transcription Factor Binding","volume":"25","author":"Kaltreider","year":"1999","journal-title":"Mol. Carcinog."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.tox.2008.07.052","article-title":"Chromium(III) Complexes Inhibit Transcription Factors Binding to DNA and Associated Gene Expression","volume":"251","author":"Raja","year":"2008","journal-title":"Toxicology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.gene.2003.08.012","article-title":"Characterization of the Role of Sp1 and NF-Y in Differential Regulation of PTTG\/Securin Expression in Tumor Cells","volume":"322","author":"Clem","year":"2003","journal-title":"Gene"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1016\/j.febslet.2010.01.049","article-title":"Tumor Suppressor Activity of KLF6 Mediated by Downregulation of the PTTG1 Oncogene","volume":"584","author":"Lee","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1002\/mc.20697","article-title":"Aberrant DNA Methylation of Some Tumor Suppressor Genes in Lung Cancers from Workers with Chromate Exposure: DNA methylation of tumor suppressor genes","volume":"50","author":"Ali","year":"2011","journal-title":"Mol. Carcinog."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.lungcan.2006.05.022","article-title":"The Reduced Expression and Aberrant Methylation of p16INK4a in Chromate Workers with Lung Cancer","volume":"53","author":"Kondo","year":"2006","journal-title":"Lung Cancer"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.toxlet.2016.03.003","article-title":"Methylation Levels of P16 and TP53 That Are Involved in DNA Strand Breakage of 16HBE Cells Treated by Hexavalent Chromium","volume":"249","author":"Hu","year":"2016","journal-title":"Toxicol. Lett."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1080\/15592294.2018.1454243","article-title":"Chromium Disrupts Chromatin Organization and CTCF Access to Its Cognate Sites in Promoters of Differentially Expressed Genes","volume":"13","author":"VonHandorf","year":"2018","journal-title":"Epigenetics"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.semcancer.2021.07.009","article-title":"Hexavalent Chromium Disrupts Chromatin Architecture","volume":"76","author":"VonHandorf","year":"2021","journal-title":"Semin. Cancer Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"115890","DOI":"10.1016\/j.taap.2022.115890","article-title":"Particulate Hexavalent Chromium Alters microRNAs in Human Lung Cells That Target Key Carcinogenic Pathways","volume":"438","author":"Speer","year":"2022","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.mrgentox.2004.02.009","article-title":"Chromium Is the Proximate Clastogenic Species for Lead Chromate-Induced Clastogenicity in Human Bronchial Cells","volume":"560","author":"Wise","year":"2004","journal-title":"Mutat. Res."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1002\/cncr.11818","article-title":"Microscopic Analysis of Chromium Accumulation in the Bronchi and Lung of Chromate Workers","volume":"98","author":"Kondo","year":"2003","journal-title":"Cancer"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.taap.2008.10.010","article-title":"Zinc Chromate Induces Chromosome Instability and DNA Double Strand Breaks in Human Lung Cells","volume":"234","author":"Xie","year":"2009","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1093\/toxsci\/kfab019","article-title":"Particulate Hexavalent Chromium Inhibits E2F1 Leading to Reduced RAD51 Nuclear Foci Formation in Human Lung Cells","volume":"181","author":"Speer","year":"2021","journal-title":"Toxicol. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/256\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:41:05Z","timestamp":1760132465000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/1\/256"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,23]]},"references-count":115,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["ijms25010256"],"URL":"https:\/\/doi.org\/10.3390\/ijms25010256","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,23]]}}}