van Bokhoven H, McKeon FMutations in the p53 homolog p63: allele-specific developmental syndromes in humans. Trends Mol Med 8:133-139

Dept of Human Genetics, University Medical Center Nijmegen, The Netherlands.
Trends in Molecular Medicine (Impact Factor: 9.45). 04/2002; 8(3):133-9. DOI: 10.1016/S1471-4914(01)02260-2
Source: PubMed


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.

4 Reads
  • Source
    • "Indeed, p63-null mice display severe defects in epithelial development (Mills et al., 1999; Yang et al., 1999). Genetic studies suggest that mutations in p63 contribute to the pathogenesis of a wide range of ectodermal dysplasias (EDs), characterized by ectodermal malformations and hypoplasias (Celli et al., 1999; Koster, 2010; Rinne et al., 2007; van Bokhoven and McKeon, 2002), and we have recently noted decreased p63 expression in chronic equine laminitis in which the proliferative epidermal layers appear dysplastic (Carter et al., 2011). Thus, it is clear that p63 plays a key role in both the normal physiology and pathophysiology of the epidermis. "
    [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.
    Full-text · Article · Dec 2014 · Development
  • Source
    • "In the EEC spectrum syndromes, the position and type of p63 mutation (frameshift, missense, deletion) correlate with the observed phenotype. p63 mutations causing EEC are usually not found in AEC, LMS, and SHFM [16–19]. The vast majority of EEC mutations are missense mutations in the DBD, generating aminoacid substitutions in the residues predicted to contact DNA. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The p53-related transcription factor p63 is critically important for basic cellular functions during development of the ectoderm and derived structure and tissues, including skin, limb, palate, and hair. On the one side, p63 is required to sustain the proliferation of keratinocyte progenitors, while on the other side it is required for cell stratification, commitment to differentiate, cell adhesion, and epithelial-mesenchymal signaling. Molecules that are components or regulators of the p63 pathway(s) are rapidly being identified, and it comes with no surprise that alterations in the p63 pathway lead to congenital conditions in which the skin and other ectoderm-derived structures are affected. In this paper, we summarize the current knowledge of the molecular and cellular regulations centered on p63, derived from the comprehension of p63-linked human diseases and the corresponding animal models, as well as from cellular models and high-throughput molecular approaches. We point out common themes and features, that allow to speculate on the possible role of p63 downstream events and their potential exploitation in future attempts to correct the congenital defect in preclinical studies.
    Full-text · Article · May 2011 · BioMed Research International
  • Source
    • "Their main functions have been shown to be critical for development and differentiation. p63 has been shown to be essential for limb, skin and craniofacial morphogenesis [23-27]; and p73 has been shown to be involved in regulation of both the stress response and development [28]. Phylogenetic analysis of these members suggests that p53 might have evolved from an ancestral p63/p73 like gene [29,30]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The N terminal transactivation domain of p53 is regulated by ligases and coactivator proteins. The functional conformation of this region appears to be an alpha helix which is necessary for its appropriate interactions with several proteins including MDM2 and p300. Folding simulation studies have been carried out to examine the propensity and stability of this region and are used to understand the differences between the family members with the ease of helix formation following the order p53 > p73 > p63. It is clear that hydrophobic clusters control the kinetics of helix formation, while electrostatic interactions control the thermodynamic stability of the helix. Differences in these interactions between the family members may partially account for the differential binding to, and regulation by, MDM2 (and MDMX). Phosphorylations of the peptides further modulate the stability of the helix and control associations with partner proteins.
    Full-text · Article · Feb 2010 · BMC Genomics
Show more