title: The carboxy-terminus of p63 links cell cycle control and the proliferative potential of epidermal progenitor cells.
abstract: The transcription factor p63 (Trp63) plays a key role in homeostasis and regeneration of the skin. The p63 gene is transcribed from dual promoters, generating TAp63 isoforms with growth suppressive functions and dominant-negative ΔNp63 isoforms with opposing properties. p63 also encodes multiple carboxy (C)-terminal variants. Although mutations of C-terminal variants have been linked to the pathogenesis of p63-associated ectodermal disorders, the physiological role of the p63 C-terminus is poorly understood. We report here that deletion of the p63 C-terminus in mice leads to ectodermal malformation and hypoplasia, accompanied by a reduced proliferative capacity of epidermal progenitor cells. Notably, unlike the p63-null condition, we find that p63 C-terminus deficiency promotes expression of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) (Cdkn1a), a factor associated with reduced proliferative capacity of both hematopoietic and neuronal stem cells. These data suggest that the p63 C-terminus plays a key role in the cell cycle progression required to maintain the proliferative potential of stem cells of many different lineages. Mechanistically, we show that loss of Cα, the predominant C-terminal p63 variant in epithelia, promotes the transcriptional activity of TAp63 and also impairs the dominant-negative activity of ΔNp63, thereby controlling p21(Waf1/Cip1) expression. We propose that the p63 C-terminus links cell cycle control and the proliferative potential of epidermal progenitor cells via mechanisms that equilibrate TAp63 and ΔNp63 isoform function.
authors.affiliation: Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Suzuki
authors.affiliation: Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Raju
authors.initials: R
authors.lastname: Sahu
authors.affiliation: Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA.
authors.forename: N Adrian
authors.initials: NA
authors.lastname: Leu
authors.affiliation: Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104, USA Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA msenoo@vet.upenn.edu.
authors.forename: Makoto
authors.initials: M
authors.lastname: Senoo
mesh_terms: D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D018797:Cell Cycle Proteins / Q000378:metabolism*; D049109:Cell Proliferation / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D000078404:Epidermal Cells; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D017931:DNA Primers; D010750:Phosphoproteins; D020033:Protein Isoforms; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D001973:Bromodeoxyuridine
keywords: Cell cycle; Epithelia; Mouse; Proliferation; Stem cells; p21; p63