{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T12:07:44Z","timestamp":1793362064989,"version":"4.5.0"},"reference-count":33,"publisher":"National Academy of Sciences","issue":"6","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,2,5]]},"abstract":"<jats:p>\n                    p53 and p63 share extensive sequence and structure homology.\n                    <jats:italic>p53<\/jats:italic>\n                    is frequently mutated in cancer, whereas mutations in\n                    <jats:italic>p63<\/jats:italic>\n                    cause developmental disorders manifested in ectodermal dysplasia, limb defects, and orofacial clefting. We have established primary adult skin keratinocytes from ectrodactyly, ectodermal dysplasia, and cleft lip\/palate (EEC) syndrome patients with\n                    <jats:italic>p63<\/jats:italic>\n                    mutations as an in vitro human model to study the disease mechanism in the skin of EEC patients. We show that these patient keratinocytes cultured either in submerged 2D cultures or in 3D skin equivalents have impaired epidermal differentiation and stratification. Treatment of these patient keratinocytes with the mutant p53-targeting compound APR-246\/PRIMA-1\n                    <jats:sup>MET<\/jats:sup>\n                    (p53 reactivation and induction of massive apoptosis) that has been successfully tested in a phase I\/II clinical trial in cancer patients partially but consistently rescued morphological features and gene expression during epidermal stratification in both 2D and 3D models. This rescue coincides with restoration of p63 target-gene expression. Our data show that EEC patient keratinocytes with p63 mutations can be used for characterization of the abnormal molecular circuitry in patient skin and may open possibilities for the design of novel pharmacological treatment strategies for patients with mutant\n                    <jats:italic>p63<\/jats:italic>\n                    -associated developmental abnormalities.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1201993110","type":"journal-article","created":{"date-parts":[[2013,1,25]],"date-time":"2013-01-25T23:14:46Z","timestamp":1359155686000},"page":"2157-2162","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":39,"title":["APR-246\/PRIMA-1\n                    <sup>MET<\/sup>\n                    rescues epidermal differentiation in skin keratinocytes derived from EEC syndrome patients with\n                    <i>p63<\/i>\n                    mutations"],"prefix":"10.1073","volume":"110","author":[{"given":"Jinfeng","family":"Shen","sequence":"first","affiliation":[{"name":"Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-171 76 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen H.","family":"van den Bogaard","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen Institute for Infection, Inflammation and Immunity, 6525 GA Nijmegen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evelyn N.","family":"Kouwenhoven","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir J. N.","family":"Bykov","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-171 76 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuula","family":"Rinne","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-171 76 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geuranne S.","family":"Tjabringa","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen Institute for Infection, Inflammation and Immunity, 6525 GA Nijmegen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Gilissen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon J.","family":"van Heeringen","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost","family":"Schalkwijk","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, Nijmegen Institute for Infection, Inflammation and Immunity, 6525 GA Nijmegen, The Netherlands;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"van Bokhoven","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klas G.","family":"Wiman","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology, Cancer Center Karolinska, Karolinska Institutet, SE-171 76 Stockholm, Sweden;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands; and"},{"name":"Department of Molecular Developmental Biology, Faculty of Science, Centre for Molecular Life Sciences, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,1,25]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2007.10.001"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/19539"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/19531"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2011.84"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.4161\/cc.6.3.3797"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(02)00166-1"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.4161\/cc.6.3.3796"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81646-3"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2010.09859.x"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1165104"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2010.159"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2010.03.154"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/emmm.201100199"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.011759"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31271"},{"key":"e_1_3_3_16_2","first-page":"7","article-title":"P53 and prognosis: New insights and further complexity","volume":"120","author":"Vousden KH","year":"2005","unstructured":"KH Vousden, C Prives, P53 and prognosis: New insights and further complexity. 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