title: Differential roles of p63 isoforms in epidermal development: selective genetic complementation in p63 null mice.
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.
authors.affiliation: Biochemistry Laboratory, IDI-IRCCS, c/o University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Candi
authors.forename: A
authors.initials: A
authors.lastname: Rufini
authors.forename: A
authors.initials: A
authors.lastname: Terrinoni
authors.forename: D
authors.initials: D
authors.lastname: Dinsdale
authors.forename: M
authors.initials: M
authors.lastname: Ranalli
authors.forename: A
authors.initials: A
authors.lastname: Paradisi
authors.forename: V
authors.initials: V
authors.lastname: De Laurenzi
authors.forename: L G
authors.initials: LG
authors.lastname: Spagnoli
authors.forename: M V
authors.initials: MV
authors.lastname: Catani
authors.forename: S
authors.initials: S
authors.lastname: Ramadan
authors.forename: R A
authors.initials: RA
authors.lastname: Knight
authors.forename: G
authors.initials: G
authors.lastname: Melino
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D004817:Epidermis / Q000196:embryology / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D000091344:Filaggrin Proteins; D020869:Gene Expression Profiling / Q000379:methods; D018507:Gene Expression Regulation, Developmental; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D053547:Keratin-14 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000196:embryology / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D053547:Keratin-14; C507446:Krt14 protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; D015534:Trans-Activators; C486419:Trp63 protein, mouse; C064554:loricrin