{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:27:51Z","timestamp":1792672071481,"version":"4.5.0"},"reference-count":41,"publisher":"The Company of Biologists","issue":"13","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,7,1]]},"abstract":"<jats:p>Heterozygous mutations of p63, a key transcription factor in epithelial development, are causative in a variety of human ectodermal dysplasia disorders. Although the mutation spectrum of these disorders displays a striking genotype\u2013phenotype association, the molecular basis for this association is only superficially known. Here, we characterize the transcriptional activity and protein stability of \u0394Np63 mutants (that is, mutants of a p63 isoform that lacks the N-terminal transactivation domain) that are found in ectrodactyly\u2013ectodermal dysplasia\u2013cleft syndrome (EEC), ankyloblepharon\u2013ectodermal dysplasia\u2013clefting syndrome (AEC) and nonsyndromic split-hand\/split-foot malformation (SHFM). DNA-binding and sterile alpha motif (SAM) domain mutants accumulate in the skin of EEC and AEC syndrome patients, respectively, and show extended half lives in vitro. By contrast, C-terminal mutations found in SHFM patients have half-lives similar to that of the wild-type protein. The increased half-life of EEC and AEC mutant proteins was reverted by overexpression of wild-type \u0394Np63. Interestingly, the mutant proteins exhibit normal binding to and degradation by the E3 ubiquitin ligase Itch. Finally, EEC and AEC mutant proteins have reduced transcriptional activity on several skin-specific gene promoters, whereas SHFM mutant proteins are transcriptionally active. Our results, therefore, provide evidence for a regulatory feedback mechanism for p63 that links transcriptional activity to regulation of protein homeostasis by an unknown mechanism. Disruption of this regulatory mechanism might contribute to the pathology of p63-related developmental disorders.<\/jats:p>","DOI":"10.1242\/jcs.079327","type":"journal-article","created":{"date-parts":[[2011,6,8]],"date-time":"2011-06-08T04:18:56Z","timestamp":1307506736000},"page":"2200-2207","source":"Crossref","is-referenced-by-count":58,"title":["Differential altered stability and transcriptional activity of \u0394Np63 mutants in distinct ectodermal dysplasias"],"prefix":"10.1242","volume":"124","author":[{"given":"Gareth","family":"Browne","sequence":"first","affiliation":[{"name":"Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Cipollone","sequence":"additional","affiliation":[{"name":"Biochemistry Laboratory, IDI-IRCCS, c\/o University of Rome \u2018Tor Vergata\u2019, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Maria","family":"Lena","sequence":"additional","affiliation":[{"name":"Biochemistry Laboratory, IDI-IRCCS, c\/o University of Rome \u2018Tor Vergata\u2019, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Serra","sequence":"additional","affiliation":[{"name":"Biochemistry Laboratory, IDI-IRCCS, c\/o University of Rome \u2018Tor Vergata\u2019, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiqing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"van Bokhoven","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"D\u00f6tsch","sequence":"additional","affiliation":[{"name":"Institute of Biophysical Chemistry, Goethe University of Frankfurt, 60438 Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Merico","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Science and Biotechnology, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Mantovani","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Science and Biotechnology, University of Milan, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Terrinoni","sequence":"additional","affiliation":[{"name":"Biochemistry Laboratory, IDI-IRCCS, c\/o University of Rome \u2018Tor Vergata\u2019, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Knight","sequence":"additional","affiliation":[{"name":"Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Candi","sequence":"additional","affiliation":[{"name":"Biochemistry Laboratory, IDI-IRCCS, c\/o University of Rome \u2018Tor Vergata\u2019, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerry","family":"Melino","sequence":"additional","affiliation":[{"name":"Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK"},{"name":"Biochemistry Laboratory, IDI-IRCCS, c\/o University of Rome \u2018Tor Vergata\u2019, 00133 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042521363398600_R1","doi-asserted-by":"crossref","first-page":"790","DOI":"10.4161\/cc.4.6.1694","article-title":"Destabilization of DeltaNp63alpha by Nedd4-mediated ubiquitination and Ubc9-mediated sumoylation, and its implications on dorsoventral patterning of the zebrafish embryo","volume":"4","author":"Bakkers","year":"2005","journal-title":"Cell Cycle"},{"key":"2021042521363398600_R2","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1093\/bioinformatics\/19.2.185","article-title":"A comparison of normalization methods for high density oligonucleotide array data based on variance and bias","volume":"19","author":"Bolstad","year":"2003","journal-title":"Bioinformatics"},{"key":"2021042521363398600_R3","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1038\/sj.cdd.4401926","article-title":"Differential roles of p63 isoforms in epidermal development: selective genetic complementation in p63 null mice","volume":"13","author":"Candi","year":"2006","journal-title":"Cell Death Differ."},{"key":"2021042521363398600_R4","doi-asserted-by":"crossref","first-page":"274","DOI":"10.4161\/cc.6.3.3797","article-title":"TAp63 and DeltaNp63 in cancer and epidermal development","volume":"6","author":"Candi","year":"2007","journal-title":"Cell Cycle"},{"key":"2021042521363398600_R5","doi-asserted-by":"crossref","first-page":"11999","DOI":"10.1073\/pnas.0703458104","article-title":"DeltaNp63 regulates thymic development through enhanced expression of FgfR2 and Jag2","volume":"104","author":"Candi","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042521363398600_R6","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/ncb1420","article-title":"p63 regulates an adhesion programme and cell survival in epithelial cells","volume":"8","author":"Carroll","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"2021042521363398600_R7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0092-8674(00)81646-3","article-title":"Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome","volume":"99","author":"Celli","year":"1999","journal-title":"Cell"},{"key":"2021042521363398600_R8","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1385\/CBB:44:3:475","article-title":"NMR structure of the p63 SAM domain and dynamical properties of G534V and T537P pathological mutants, identified in the AEC syndrome","volume":"44","author":"Cicero","year":"2006","journal-title":"Cell Biochem. Biophys."},{"key":"2021042521363398600_R9","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.1038\/sj.onc.1204427","article-title":"p63alpha and DeltaNp63alpha can induce cell cycle arrest and apoptosis and differentially regulate p53 target genes","volume":"20","author":"Dohn","year":"2001","journal-title":"Oncogene"},{"key":"2021042521363398600_R10","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1093\/hmg\/11.7.799","article-title":"Gain-of-function mutation in ADULT syndrome reveals the presence of a second transactivation domain in p63","volume":"11","author":"Duijf","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2021042521363398600_R11","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/S1097-2765(02)00706-2","article-title":"REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species","volume":"10","author":"Ellisen","year":"2002","journal-title":"Mol. Cell"},{"key":"2021042521363398600_R12","doi-asserted-by":"crossref","first-page":"23906","DOI":"10.1074\/jbc.M300746200","article-title":"P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome","volume":"278","author":"Fomenkov","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021042521363398600_R13","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1093\/bioinformatics\/btg405","article-title":"affy-analysis of Affymetrix GeneChip data at the probe level","volume":"20","author":"Gautier","year":"2004","journal-title":"Bioinformatics"},{"key":"2021042521363398600_R14","doi-asserted-by":"crossref","first-page":"183","DOI":"10.4161\/cc.4.1.1359","article-title":"The protein stability and transcriptional activity of p63alpha are regulated by SUMO-1 conjugation","volume":"4","author":"Ghioni","year":"2005","journal-title":"Cell Cycle"},{"key":"2021042521363398600_R15","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/sj.jid.5700010","article-title":"Dysregulation of TAp63 mRNA and protein levels in psoriasis","volume":"126","author":"Gu","year":"2006","journal-title":"J. Invest. Dermatol."},{"key":"2021042521363398600_R16","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.4161\/cc.3.12.1290","article-title":"Altered sumoylation of p63alpha contributes to the split-hand\/foot malformation phenotype","volume":"3","author":"Huang","year":"2004","journal-title":"Cell Cycle"},{"key":"2021042521363398600_R17","doi-asserted-by":"crossref","first-page":"1440","DOI":"10.4161\/cc.4.10.2086","article-title":"AEC-associated p63 mutations lead to alternative splicing\/protein stabilization of p63 and modulation of Notch signaling","volume":"4","author":"Huang","year":"2005","journal-title":"Cell Cycle"},{"key":"2021042521363398600_R18","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1242\/dev.02325","article-title":"p63 regulates multiple signalling pathways required for ectodermal organogenesis and differentiation","volume":"133","author":"Laurikkala","year":"2006","journal-title":"Development"},{"key":"2021042521363398600_R19","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1038\/cdd.2008.69","article-title":"miR-203 represses \u2018stemness\u2019 by repressing DeltaNp63","volume":"15","author":"Lena","year":"2008","journal-title":"Cell Death Differ."},{"key":"2021042521363398600_R20","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1242\/dev.011759","article-title":"Regulation of Dlx5 and Dlx6 gene expression by p63 is involved in EEC and SHFM congenital limb defects","volume":"135","author":"Lo Iacono","year":"2008","journal-title":"Development"},{"key":"2021042521363398600_R21","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1093\/hmg\/10.3.221","article-title":"Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63","volume":"10","author":"McGrath","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"2021042521363398600_R22","doi-asserted-by":"crossref","first-page":"e13984","DOI":"10.1371\/journal.pone.0013984","article-title":"Enrichment map: a network-based method for gene-set enrichment visualization and interpretation","volume":"5","author":"Merico","year":"2010","journal-title":"PLoS ONE"},{"key":"2021042521363398600_R23","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/19531","article-title":"p63 is a p53 homologue required for limb and epidermal morphogenesis","volume":"398","author":"Mills","year":"1999","journal-title":"Nature"},{"key":"2021042521363398600_R24","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1172\/JCI40267","article-title":"A regulatory feedback loop involving p63 and IRF6 links the pathogenesis of 2 genetically different human ectodermal dysplasias","volume":"120","author":"Moretti","year":"2010","journal-title":"J. Clin. Invest."},{"key":"2021042521363398600_R25","doi-asserted-by":"crossref","first-page":"e5008","DOI":"10.1371\/journal.pone.0005008","article-title":"Transcriptional network of p63 in human keratinocytes","volume":"4","author":"Pozzi","year":"2009","journal-title":"PLoS ONE"},{"key":"2021042521363398600_R26","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1242\/dev.02703","article-title":"Homeobox gene Dlx3 is regulated by p63 during ectoderm development: relevance in the pathogenesis of ectodermal dysplasias","volume":"134","author":"Radoja","year":"2007","journal-title":"Development"},{"key":"2021042521363398600_R27","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1002\/ajmg.a.31271","article-title":"Pattern of p63 mutations and their phenotypes-update","volume":"140","author":"Rinne","year":"2006","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042521363398600_R28","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1038\/sj.ejhg.5201640","article-title":"Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene","volume":"14","author":"Rinne","year":"2006","journal-title":"Eur. J. Hum. Genet."},{"key":"2021042521363398600_R29","doi-asserted-by":"crossref","first-page":"262","DOI":"10.4161\/cc.6.3.3796","article-title":"p63-associated disorders","volume":"6","author":"Rinne","year":"2007","journal-title":"Cell Cycle"},{"key":"2021042521363398600_R30","doi-asserted-by":"crossref","first-page":"1968","DOI":"10.1093\/hmg\/ddn094","article-title":"A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin\/Hay-Wells like syndromes","volume":"17","author":"Rinne","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"2021042521363398600_R31","doi-asserted-by":"crossref","first-page":"12753","DOI":"10.1073\/pnas.0603449103","article-title":"The E3 ubiquitin ligase Itch controls the protein stability of p63","volume":"103","author":"Rossi","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042521363398600_R32","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.cell.2007.02.045","article-title":"p63 Is essential for the proliferative potential of stem cells in stratified epithelia","volume":"129","author":"Senoo","year":"2007","journal-title":"Cell"},{"key":"2021042521363398600_R33","doi-asserted-by":"crossref","first-page":"8601","DOI":"10.1128\/MCB.22.24.8601-8611.2002","article-title":"A C-terminal inhibitory domain controls the activity of p63 by an intramolecular mechanism","volume":"22","author":"Serber","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"2021042521363398600_R34","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042521363398600_R35","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1172\/JCI40266","article-title":"Cooperation between the transcription factors p63 and IRF6 is essential to prevent cleft palate in mice","volume":"120","author":"Thomason","year":"2010","journal-title":"J. Clin. Invest."},{"key":"2021042521363398600_R36","doi-asserted-by":"crossref","first-page":"5105","DOI":"10.1038\/sj.emboj.7601375","article-title":"New p63 targets in keratinocytes identified by a genome-wide approach","volume":"25","author":"Vigano","year":"2006","journal-title":"EMBO J."},{"key":"2021042521363398600_R37","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1128\/MCB.23.7.2264-2276.2003","article-title":"The Delta Np63 alpha phosphoprotein binds the p21 and 14-3-3 sigma promoters in vivo and has transcriptional repressor activity that is reduced by Hay-Wells syndrome-derived mutations","volume":"23","author":"Westfall","year":"2003","journal-title":"Mol. Cell. Biol."},{"key":"2021042521363398600_R38","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/S1097-2765(00)80275-0","article-title":"p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities","volume":"2","author":"Yang","year":"1998","journal-title":"Mol. Cell"},{"key":"2021042521363398600_R39","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1038\/19539","article-title":"p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development","volume":"398","author":"Yang","year":"1999","journal-title":"Nature"},{"key":"2021042521363398600_R40","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.molcel.2006.10.018","article-title":"Relationships between p63 binding, DNA sequence, transcription activity, and biological function in human cells","volume":"24","author":"Yang","year":"2006","journal-title":"Mol. Cell"},{"key":"2021042521363398600_R41","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nature06642","article-title":"A skin microRNA promotes differentiation by repressing \u2018stemness\u2019","volume":"452","author":"Yi","year":"2008","journal-title":"Nature"}],"container-title":["Journal of Cell Science"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/124\/13\/2200\/1446573\/2200.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/124\/13\/2200\/1446573\/2200.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,25]],"date-time":"2021-04-25T22:34:32Z","timestamp":1619390072000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/jcs\/article\/124\/13\/2200\/31856\/Differential-altered-stability-and-transcriptional"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,7,1]]},"references-count":41,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2011,7,1]]}},"URL":"https:\/\/doi.org\/10.1242\/jcs.079327","relation":{},"ISSN":["1477-9137","0021-9533"],"issn-type":[{"value":"1477-9137","type":"electronic"},{"value":"0021-9533","type":"print"}],"subject":[],"published":{"date-parts":[[2011,7,1]]}}}