{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T11:18:32Z","timestamp":1785151112157,"version":"3.55.0"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"29","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020581","name":"Fondazione AIRC per la ricerca sul cancro ETS","doi-asserted-by":"publisher","award":["ID31044"],"award-info":[{"award-number":["ID31044"]}],"id":[{"id":"10.13039\/100020581","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["PNRR-MAD-2022-12375755"],"award-info":[{"award-number":["PNRR-MAD-2022-12375755"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,7,22]]},"abstract":"<jats:p>The transcription factor p63 is an essential regulator of epithelial development. Yet, the complexity at the 3\u2032UTR, which gives rise to the three distinct C-terminal protein isoforms (\u03b1, \u03b2, and \u03b3), remains unresolved and opens an investigation on the in vivo role of the C-terminus. This region, codified by exon 13, harbors genetic mutations leading to AEC syndrome. Here, we generated a mouse with a deletion of p63 exon 13 in keratin-14-expressing tissues and employed transcriptome, genome-wide occupancy, and interactome studies to characterize the role of the p63 C-terminus in vivo. In this model mouse, the p63 protein is expressed at the correct level in time and space but predominantly as the \u03b2 isoform instead of the \u03b1 isoform, thereby providing insights into the function of the C-terminus. We show that p63\u03b2 interacts more readily with the core promoter transcription machinery and p63\u03b1-depleted isoforms bind more frequently the promoter region of target genes, resulting in inappropriate overexpression of extracellular matrix organization genes in the skin. This leads to the aberrant adhesion of epidermal keratinocytes to the basal lamina and triggers systemic inflammation, growth abnormalities, and premature death. We found a significant role of the full-length \u0394Np63a isoform which cannot be substituted by the other isoforms (\u03b2 or \u03b3). Our studies highlight a crucial role for p63\u03b1 in correctly orchestrating the gene expression program to ensure proper formation of epithelia.<\/jats:p>","DOI":"10.1073\/pnas.2503866122","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T17:51:53Z","timestamp":1752774713000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["Deletion of p63 exon 13 in mice reveals C-terminal isoform\u2013specific functions in epithelial development"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6285-9927","authenticated-orcid":false,"given":"Anna Maria","family":"Lena","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1575-8725","authenticated-orcid":false,"given":"Artem","family":"Smirnov","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d","place":["Rome, Italy"]},{"name":"Biochemistry Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico\u2013Istituto Dermopatico Immacolata","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5173-4854","authenticated-orcid":false,"given":"Mara","family":"Mancini","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d","place":["Rome, 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Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9209-1207","authenticated-orcid":false,"given":"Roberta","family":"Nardacci","sequence":"additional","affiliation":[{"name":"National Institute for Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico \u201cLazzaro Spallanzani\u201d","place":["Rome, Italy"]},{"name":"Departmental Faculty of Medicine, St. Camillus International University of Health Sciences","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gian Maria","family":"Fimia","sequence":"additional","affiliation":[{"name":"National Institute for Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico \u201cLazzaro Spallanzani\u201d","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Mavilio","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome \u201cTor Vergata\u201d","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Federici","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome \u201cTor Vergata\u201d","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7351-5676","authenticated-orcid":false,"given":"Alessandro","family":"Mauriello","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Piacentini","sequence":"additional","affiliation":[{"name":"National Institute for Infectious Diseases, Istituto di Ricovero e Cura a Carattere Scientifico \u201cLazzaro Spallanzani\u201d","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9428-5972","authenticated-orcid":false,"given":"Gerry","family":"Melino","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8332-4825","authenticated-orcid":false,"given":"Eleonora","family":"Candi","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Rome \u201cTor Vergata\u201d","place":["Rome, Italy"]},{"name":"Biochemistry Laboratory, Istituto di Ricovero e Cura a Carattere Scientifico\u2013Istituto Dermopatico Immacolata","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80275-0"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/19539"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.02.045"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/19531"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cdd.4401914"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M507964200"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/11.7.799"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.01.013"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20669-0"},{"key":"e_1_3_4_10_2","first-page":"282","article-title":"The carboxy-terminus of p63 links cell cycle 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Suzuki, R. Sahu, N. A. Leu, M. Senoo, The carboxy-terminus of p63 links cell cycle control and the proliferative potential of epidermal progenitor cells. 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