Mutations in the p53 homolog p63: allele-specific developmental syndromes in humans.
ABSTRACT p63 is the most recently discovered but most ancient member of the p53 family. In marked contrast to p53, p63 is highly expressed in embryonic ectoderm and in the basal, regenerative layers of many epithelial tissues in the adult. The p63-knockout mouse dies at birth and lacks limbs, epidermis, prostate, breast and urothelial tissues, apparently owing to the loss of stem cells required for these tissues. Significantly, several dominant human syndromes involving limb development and/or ectodermal dysplasia have been mapped to chromosome 3q27 and ultimately the gene encoding p63. The heterozygous p63mutations are distinct for each of the syndromes and are thought to act through both dominant-negative and gain-of-function mechanisms rather than a loss-of-function haploinsufficiency. The allele specificity of these syndromes offers unique molecular insights into the poorly understood actions of p63 in limb development, ectodermal-mesodermal interactions and stem cell maintenance.
- SourceAvailable from: Makoto Senoo[Show abstract] [Hide abstract]
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. © 2015. Published by The Company of Biologists Ltd.Development 12/2014; 142(2). DOI:10.1242/dev.118307 · 6.27 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The transcription factor p63 is commonly over-expressed in squamous cell carcinomas of the head and neck (SCCHN). By microarray analysis of p63-siRNA-treated SCCHN cells we identified 127 genes whose expression relies on over-expression of p63. More than 20% of these genes are involved in cell motility. Chromatin immunoprecipitation and reporter assay revealed PAI-1 and AQP3 as direct p63 transcriptional targets. In addition to PAI-1, most of the key cell motility-related molecules are up-regulated by p63, such as MMP14 and LGALS1. Our findings indicate a contribution by p63 in cell invasion and migration, supporting an oncogenic role for p63 in SCCHN.Cancer Letters 06/2008; 263(1):26-34. DOI:10.1016/j.canlet.2007.12.011 · 5.02 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Regulation of p53 by the ubiquitin-proteasomal pathway has been studied considerably. Studies have also demonstrated that the ubiquitin-like proteins SUMO-1 and NEDD8 modify p53. Similarly, p63 and p73 are subject to regulation by ubiquitin and ubiquitin-like modifications, and perturbations of these pathways in the regulation of the p53 family have been implicated in tumorigenesis and developmental abnormalities. Here, we provide an overview of the current understanding of the regulation of the p53 family by covalent modification by ubiquitin, SUMO-1, and NEDD8.Neoplasia (New York, N.Y.) 09/2006; 8(8):655-66. DOI:10.1593/neo.06439 · 5.40 Impact Factor