{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T13:26:35Z","timestamp":1780579595825,"version":"3.54.1"},"reference-count":46,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,5,10]],"date-time":"2019-05-10T00:00:00Z","timestamp":1557446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE018106"],"award-info":[{"award-number":["R01DE018106"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE027648"],"award-info":[{"award-number":["R01DE027648"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005520","name":"Byrd Polar Research Center, Ohio State University","doi-asserted-by":"publisher","award":["21-100300"],"award-info":[{"award-number":["21-100300"]}],"id":[{"id":"10.13039\/100005520","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Fluoride overexposure is an environmental health hazard and can cause enamel and skeletal fluorosis. Previously we demonstrated that fluoride increased acetylated-p53 and its downstream target p21 in ameloblast-derived LS8 cells. However, p21 function in fluoride toxicity is not well characterized. This study seeks to gain a better understanding of how p53 down-stream mediators, p21 and MDM2, respond to fluoride toxicity. LS8 cells were treated with NaF with\/without MG-132 (proteasome inhibitor) or Nutlin-3a (MDM2 antagonist). NaF treatment for 2\u20136 h increased phospho-p21, which can inhibit apoptosis. However, phospho-p21 and p21 were decreased by NaF at 24 h, even though p21 mRNA was significantly increased at this time point. MG-132 reversed the fluoride-mediated p21 decrease, indicating that fluoride facilitates p21 proteasomal degradation. MG-132 suppressed fluoride-induced caspase-3 cleavage, suggesting that the proteasome plays a pro-apoptotic role in fluoride toxicity. NaF increased phospho-MDM2 in vitro and in mouse ameloblasts in vivo. Nutlin-3a suppressed NaF-mediated MDM2-p21 binding to reverse p21 degradation which increased phospho-p21. This suppressed apoptosis after 24 h NaF treatment. These results suggest that MDM2-mediated p21 proteasomal degradation with subsequent phospho-p21 attenuation contributes to fluoride-induced apoptosis. Inhibition of MDM2-mediated p21 degradation may be a potential therapeutic target to mitigate fluoride toxicity.<\/jats:p>","DOI":"10.3390\/cells8050436","type":"journal-article","created":{"date-parts":[[2019,5,13]],"date-time":"2019-05-13T05:35:39Z","timestamp":1557725739000},"page":"436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["MDM2-Mediated p21 Proteasomal Degradation Promotes Fluoride Toxicity in Ameloblasts"],"prefix":"10.3390","volume":"8","author":[{"given":"Huidan","family":"Deng","sequence":"first","affiliation":[{"name":"Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA"},{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2963-531X","authenticated-orcid":false,"given":"Hengmin","family":"Cui","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Sichuan Agricultural University, Wenjiang, Chengdu 611130, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2052-6299","authenticated-orcid":false,"given":"John D.","family":"Bartlett","sequence":"additional","affiliation":[{"name":"Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1732-0663","authenticated-orcid":false,"given":"Maiko","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, The Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,5,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1177\/154411130201300206","article-title":"Dental Fluorosis: Chemistry and Biology","volume":"13","author":"Aoba","year":"2002","journal-title":"Crit. 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