{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:17:21Z","timestamp":1778199441266,"version":"3.51.4"},"reference-count":41,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T00:00:00Z","timestamp":1748476800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Telethon Foundation (Italy)","award":["GGP20124"],"award-info":[{"award-number":["GGP20124"]}]},{"name":"the Telethon Foundation (Italy)","award":["CUP D53D23014500006"],"award-info":[{"award-number":["CUP D53D23014500006"]}]},{"name":"the European Union\u2014Next Generation EU","award":["GGP20124"],"award-info":[{"award-number":["GGP20124"]}]},{"name":"the European Union\u2014Next Generation EU","award":["CUP D53D23014500006"],"award-info":[{"award-number":["CUP D53D23014500006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mutations in the TP63 gene cause several syndromic disorders, including ankyloblepharon\u2013ectodermal defects\u2013cleft lip\/palate (AEC) syndrome, characterized by severe skin erosions, cleft palate, and ectodermal dysplasia. These mutations often affect the carboxy-terminal sterile-\u03b1-motif (SAM) domain of the p63 protein, leading to domain misfolding, protein aggregation, and impaired transcriptional activity. To dissect the molecular mechanisms underlying AEC pathogenesis, we investigated primary keratinocytes derived from p63L514F mutant mice, which carry a SAM domain mutation associated with AEC syndrome. p63L514F keratinocytes exhibited significantly reduced proliferation compared to wild-type controls, as indicated by decreased 5-ethynyl-2\u2032-deoxyuridine (EdU) incorporation, decreased Cyclin D1 and Cyclin D2 expression, and an increase in the cell-cycle inhibitors p21 and p27. Furthermore, p63L514F keratinocytes showed increased cell death, elevated reactive oxygen species (ROS) levels, and a decreased reduced (GSH) and oxidized (GSSG) glutathione (GSH\/GSSG) ratio, indicating oxidative stress. This stress response was accompanied by a marked reduction in Solute Carrier Family 7 Member 11 (Slc7a11), a critical regulator of antioxidant defense. We further identified Slc7a11 as a likely direct transcriptional target of p63: p63 depletion reduced Slc7a11 expression, and chromatin immunoprecipitation uncovered an evolutionary conserved p63-binding enhancer upstream of the Slc7a11 promoter. Together, our findings demonstrate that p63 mutations causative of AEC syndrome impair keratinocyte proliferation, promote cell death via oxidative stress, and compromised antioxidant defenses, revealing a dual role for p63 in sustaining skin homeostasis.<\/jats:p>","DOI":"10.3390\/ijms26115231","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T07:46:26Z","timestamp":1748504786000},"page":"5231","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Ankyloblepharon\u2013Ectodermal Defects\u2013Cleft Lip\/Palate Syndrome-Linked p63 Mutations Disrupt Keratinocyte Proliferation and Survival Through Oxidative Stress and Impaired Slc7a11 Expression"],"prefix":"10.3390","volume":"26","author":[{"given":"Daniela","family":"Di Girolamo","sequence":"first","affiliation":[{"name":"Department of Biology, University of Naples Federico II, 80126 Naples, Italy"},{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Palumbo","sequence":"additional","affiliation":[{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, 80145 Naples, Italy"},{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dario","family":"Antonini","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Naples Federico II, 80126 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludovica","family":"D\u2019Auria","sequence":"additional","affiliation":[{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vincenza","family":"Cerbone","sequence":"additional","affiliation":[{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6162-5819","authenticated-orcid":false,"given":"Tommaso","family":"Porcelli","sequence":"additional","affiliation":[{"name":"Department of Public Health, University of Naples Federico II, 80131 Napoli, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4571-1060","authenticated-orcid":false,"given":"Federica","family":"Cavallo","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Molecular Biotechnology Center \u201cGuido Tarone\u201d, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4439-9709","authenticated-orcid":false,"given":"Enzo","family":"Calautti","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy"},{"name":"Molecular Biotechnology Center \u201cGuido Tarone\u201d, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9787-4836","authenticated-orcid":false,"given":"Chiara","family":"Riganti","sequence":"additional","affiliation":[{"name":"Molecular Biotechnology Center \u201cGuido Tarone\u201d, University of Turin, 10126 Turin, Italy"},{"name":"Department of Oncology, University of Turin, 10126 Turin, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0905-5123","authenticated-orcid":false,"given":"Caterina","family":"Missero","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Naples Federico II, 80126 Naples, Italy"},{"name":"CEINGE Biotecnologie Avanzate Franco Salvatore, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.jid.2024.08.011","article-title":"Molecular and Cellular Function of p63 in Skin Development and Genetic Diseases","volume":"145","author":"Missero","year":"2025","journal-title":"J. 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