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dc.contributor.authorKubota, Kaori
dc.contributor.authorLee, Daniel H.
dc.contributor.authorTsuchiya, Masahiro
dc.contributor.authorYoung, Conan S.
dc.contributor.authorEverett, Eric T.
dc.contributor.authorMartinez-Mier, Esperanza A.
dc.contributor.authorSnead, Malcolm
dc.contributor.authorNguyen, Linh X.
dc.contributor.authorUrano, Fumihiko
dc.contributor.authorBartlett, John D.
dc.date2022-08-11T08:10:15.000
dc.date.accessioned2022-08-23T17:01:02Z
dc.date.available2022-08-23T17:01:02Z
dc.date.issued2005-04-26
dc.date.submitted2011-04-19
dc.identifier.citationJ Biol Chem. 2005 Jun 17;280(24):23194-202. Epub 2005 Apr 23. <a href="http://dx.doi.org/10.1074/jbc.M503288200">Link to article on publisher's site</a>
dc.identifier.issn0021-9258 (Linking)
dc.identifier.doi10.1074/jbc.M503288200
dc.identifier.pmid15849362
dc.identifier.urihttp://hdl.handle.net/20.500.14038/43918
dc.description.abstractThe mechanism of how fluoride causes fluorosis remains unknown. Exposure to fluoride can inhibit protein synthesis, and this may also occur by agents that cause endoplasmic reticulum (ER) stress. When translated proteins fail to fold properly or become misfolded, ER stress response genes are induced that together comprise the unfolded protein response. Because ameloblasts are responsible for dental enamel formation, we used an ameloblast-derived cell line (LS8) to characterize specific responses to fluoride treatment. LS8 cells were growth-inhibited by as little as 1.9-3.8 ppm fluoride, whereas higher doses induced ER stress and caspase-mediated DNA fragmentation. Growth arrest and DNA damage-inducible proteins (GADD153/CHOP, GADD45alpha), binding protein (BiP/glucose-responsive protein 78 (GRP78), the non-secreted form of carbonic anhydrase VI (CA-VI), and active X-box-binding protein-1 (Xbp-1) were all induced significantly after exposure to 38 ppm fluoride. Unexpectedly, DNA fragmentation increased when GADD153 expression was inhibited by short interfering RNA treatment but remained unaffected by transient GADD153 overexpression. Analysis of control and GADD153(-/-) embryonic fibroblasts demonstrated that caspase-3 mediated the increased DNA fragmentation observed in the GADD153 null cells. We also demonstrate that mouse incisor ameloblasts are sensitive to the toxic effects of high dose fluoride in drinking water. Activated Ire1 initiates an ER stress response pathway, and mouse ameloblasts were shown to express activated Ire1. Ire1 levels appeared induced by fluoride treatment, indicating that ER stress may play a role in dental fluorosis. Low dose fluoride, such as that present in fluoridated drinking water, did not induce ER stress.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=15849362&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1074/jbc.M503288200
dc.subjectAlternative Splicing
dc.subjectAmeloblasts
dc.subjectAnimals
dc.subjectApoptosis
dc.subjectBlotting, Northern
dc.subjectBlotting, Western
dc.subjectCCAAT-Enhancer-Binding Proteins
dc.subjectCarbonic Anhydrases
dc.subjectCaspase 3
dc.subjectCaspases
dc.subjectCell Cycle Proteins
dc.subjectCell Line
dc.subjectCell Proliferation
dc.subjectCell Survival
dc.subjectColoring Agents
dc.subjectDNA Damage
dc.subjectDNA Fragmentation
dc.subjectDNA, Complementary
dc.subjectDNA-Binding Proteins
dc.subjectDental Enamel
dc.subjectDose-Response Relationship, Drug
dc.subjectDown-Regulation
dc.subjectEndoplasmic Reticulum
dc.subjectEndoribonucleases
dc.subjectEnzyme-Linked Immunosorbent Assay
dc.subjectEpithelium
dc.subjectFibroblasts
dc.subjectFluorides
dc.subjectHeat-Shock Proteins
dc.subjectImmunohistochemistry
dc.subjectIn Situ Nick-End Labeling
dc.subjectMembrane Proteins
dc.subjectMice
dc.subjectMice, Transgenic
dc.subjectMolecular Chaperones
dc.subjectNuclear Proteins
dc.subjectProtein Binding
dc.subjectProtein Biosynthesis
dc.subjectProtein Folding
dc.subjectProtein-Serine-Threonine Kinases
dc.subjectRNA, Small Interfering
dc.subjectReverse Transcriptase Polymerase Chain Reaction
dc.subjectSodium Fluoride
dc.subjectSwine
dc.subjectTetrazolium Salts
dc.subjectThiazoles
dc.subjectTime Factors
dc.subjectTranscription Factor CHOP
dc.subjectTranscription Factors
dc.subjectGenetics and Genomics
dc.titleFluoride induces endoplasmic reticulum stress in ameloblasts responsible for dental enamel formation
dc.typeJournal Article
dc.source.journaltitleThe Journal of biological chemistry
dc.source.volume280
dc.source.issue24
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/pgfe_pp/129
dc.identifier.contextkey1946784
html.description.abstract<p>The mechanism of how fluoride causes fluorosis remains unknown. Exposure to fluoride can inhibit protein synthesis, and this may also occur by agents that cause endoplasmic reticulum (ER) stress. When translated proteins fail to fold properly or become misfolded, ER stress response genes are induced that together comprise the unfolded protein response. Because ameloblasts are responsible for dental enamel formation, we used an ameloblast-derived cell line (LS8) to characterize specific responses to fluoride treatment. LS8 cells were growth-inhibited by as little as 1.9-3.8 ppm fluoride, whereas higher doses induced ER stress and caspase-mediated DNA fragmentation. Growth arrest and DNA damage-inducible proteins (GADD153/CHOP, GADD45alpha), binding protein (BiP/glucose-responsive protein 78 (GRP78), the non-secreted form of carbonic anhydrase VI (CA-VI), and active X-box-binding protein-1 (Xbp-1) were all induced significantly after exposure to 38 ppm fluoride. Unexpectedly, DNA fragmentation increased when GADD153 expression was inhibited by short interfering RNA treatment but remained unaffected by transient GADD153 overexpression. Analysis of control and GADD153(-/-) embryonic fibroblasts demonstrated that caspase-3 mediated the increased DNA fragmentation observed in the GADD153 null cells. We also demonstrate that mouse incisor ameloblasts are sensitive to the toxic effects of high dose fluoride in drinking water. Activated Ire1 initiates an ER stress response pathway, and mouse ameloblasts were shown to express activated Ire1. Ire1 levels appeared induced by fluoride treatment, indicating that ER stress may play a role in dental fluorosis. Low dose fluoride, such as that present in fluoridated drinking water, did not induce ER stress.</p>
dc.identifier.submissionpathpgfe_pp/129
dc.contributor.departmentProgram in Molecular Medicine
dc.contributor.departmentProgram in Gene Function and Expression
dc.source.pages23194-202


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