Differential roles of p63 isoforms in epidermal development: selective genetic complementation in p63 null mice
Eleonora Candi,Alessandro Rufini,Alessandro Terrinoni,David Dinsdale,Marco Ranalli,Andrea Paradisi,V De Laurenzi,Luigi Giusto Spagnoli,M V Catani,Safaa M. Ramadan,Richard A. Knight,Gerry Melino,Gerry Melino +12 more
TL;DR: The two p63 isoforms appear to play distinct cooperative roles in epidermal formation, as double TAp63α/ΔNp 63α complementation showed greater patches of differentiated skin and at the ultrastructural level, there was clear reformation of a distinct basal membrane and hemidesmosomes.
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Abstract: Epidermal development requires the transcription factor p63, as p63-/- mice are born dead, without skin. The gene expresses two proteins, one with an amino-terminal transactivation domain (TAp63) and one without (deltaNp63), although their relative contribution to epidermal development is unknown. To address this issue, we reintroduced TAp63alpha and/or deltaNp63alpha under the K5 promoter into p63-/- mice by in vivo genetic complementation. Whereas p63-/- and p63-/-;TA mice showed extremely rare patches of poorly differentiated keratinocytes, p63-/-;deltaN mice showed significant epidermal basal layer formation. Double TAp63alpha/deltaNp63alpha complementation showed greater patches of differentiated skin; at the ultrastructural level, there was clear reformation of a distinct basal membrane and hemidesmosomes. At the molecular level, deltaNp63 regulated expression of genes characteristic of the basal layer (K14), interacting (by Chip, luc assay) with the third p53 consensus site. Conversely, TAp63 transcribed the upper layer's genes (Ets-1, K1, transglutaminases, involucrin). Therefore, the two p63 isoforms appear to play distinct cooperative roles in epidermal formation.
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Citations
Inhibitor of apoptosis-stimulating protein of p53 (iASPP) prevents senescence and is required for epithelial stratification
Mario Notari,Ying Hu,Sofia Koch,Min Lu,Indrika Ratnayaka,Shan Zhong,Caroline Baer,Anna Pagotto,Robert D. Goldin,Victoria Salter,Eleonora Candi,Gerry Melino,Xin Lu +12 more
TL;DR: It is observed that iASPP is able to prevent premature cellular senescence in mouse embryonic fibroblasts and is a key player in controlling epithelial stratification.
Protein aggregation of the p63 transcription factor underlies severe skin fragility in AEC syndrome.
Claudia Russo,Christian Osterburg,Anna Sirico,Dario Antonini,Raffaele Ambrosio,Julia M. Würz,Jörg Rinnenthal,Marco Ferniani,Sebastian Kehrloesser,Birgit Schäfer,Peter Güntert,Satrajit Sinha,Volker Dötsch,Caterina Missero +13 more
TL;DR: It is shown that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer.
The p63 C-terminus is essential for murine oocyte integrity.
Anna Maria Lena,Valerio Rossi,Susanne Osterburg,Artem Smirnov,Artem Smirnov,Christian Osterburg,Marcel Tuppi,Marcel Tuppi,Angela Cappello,Ivano Amelio,Ivano Amelio,Volker Dötsch,Massimo De Felici,Francesca Gioia Klinger,Margherita Annicchiarico-Petruzzelli,Herbert Valensise,Gerry Melino,Eleonora Candi +17 more
TL;DR: In this paper, a mouse model was developed to investigate how the different isoforms fulfil distinct functions at the cellular and developmental levels, and the results showed that the p63 C-terminus is essential in TAp63α-expressing primary oocytes to control cell death in vivo.
Ocular Manifestations in Patients Affected by p63-Associated Disorders: Ectrodactyly-Ectodermal Dysplasia-Clefting (EEC) and Ankyloblepharon-Ectodermal Defects-Cleft Lip Palate (AEC) Syndromes
Enzo Di Iorio,Filippo Bonelli,Raluca Bievel-Radulescu,Nicolò Decastello,Stefano Ferrari,Vanessa Barbaro,Diego Ponzin +6 more
TL;DR: The therapies supplied to patients were essential for the management of the symptoms, but unfortunately did not halt the progression of the pathology and a constant monitoring of the patients would help avoid the sudden worsening of symptoms.
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