Adult mice lacking the p53/p63 target gene PERP are not predisposed to spontaneous tumorigenesis but display features of ectodermal dysplasia syndromes

Article (PDF Available)inCell Death and Differentiation 13(9):1614-8 · October 2006with19 Reads
DOI: 10.1038/sj.cdd.4401871 · Source: PubMed

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Available from: Rebecca Ihrie, Apr 11, 2014
    • "Ectodermal dysplasia and cleft lip/ palate are part of human EEC syndrome (ectodactyly, ectodermal dysplasia and cleft lip/palate), caused by heterozygous P63 missense mutations [21]. From the data described above, it is evident that PERP is the direct molecular target of P63, and is required for stratified epithelial function in vivo [63,70,81,82] . PERP also interacts with DSP, which links IFs to the cytoskeletal network [93,98]. "
    [Show abstract] [Hide abstract] ABSTRACT: Bladder exstrophy-epispadias complex (BEEC) is a complex and debilitating congenital disease. Familial and twin studies suggest a possible genetic component in BEEC pathogenesis. Bladder mesenchyme (detrusor) development requires induction by a signal from bladder urothelium, and we and others have shown the Shh-Gli-Bmp4 signalling pathway is likely to be involved. P63 is a master regulator in epithelial stratification and is expressed in urothelium. We have shown that p63 knock-out mice undergo excessive urothelial apoptosis. Failure of mesenchymal induction by epithelium leads to BEEC. We further demonstrated that insertion/deletion (in/del) polymorphisms (1 base pair (bp) ins and 4 bp ins., and 12 bp del) in the ΔNP63 promoter reduce transcriptional efficiency, and are associated with a statistically significant increase in the risk of BEEC in humans. Furthermore, a Genome-Wide Expression Profiling (GWEP) study suggests possible involvement of PERP in human BEEC. Intriguingly, PERP is a direct target of p63 during development, and is also involved in epithelial stratification. PERP co-localizes with desmosome, and both PERP and desmosome are essential for maintaining tissue integrity by cellular adhesion and epithelial stratification. A recent study showed that PERP and desmosome expression levels are abnormal in human BEEC patients. This review describes the role of the P63 > PERP > desmosome pathway in the development of human bladder during embryogenesis. We hypothesize that disruption of this pathway may increase the risk of BEEC.
    Full-text · Article · Jun 2013
    • "Hitherto, the transmembrane protein PERP has been regarded as a constitutive molecule of the desmosomes of various stratified epithelia and consequently, the possible functions of PERP have been discussed with respect to such epithelia, notably epidermal keratinocytes (e.g., Ihrie et al. , 2006 for reviews, see Beaudry et al. 2010a for reviews, see Beaudry et al. , 2010b Dusek and Attardi 2011). These reports and discussions have included the development of PERP−/− mice, which suffer perinatal death accompanied by severe epidermalFig. "
    [Show abstract] [Hide abstract] ABSTRACT: Protein PERP (p53 apoptosis effector related to PMP-22) is a small (21.4 kDa) transmembrane polypeptide with an amino acid sequence indicative of a tetraspanin character. It is enriched in the plasma membrane and apparently contributes to cell-cell contacts. Hitherto, it has been reported to be exclusively a component of desmosomes of some stratified epithelia. However, by using a series of newly generated mono- and polyclonal antibodies, we show that protein PERP is not only present in all kinds of stratified epithelia but also occurs in simple, columnar, complex and transitional epithelia, in various types of squamous metaplasia and epithelium-derived tumors, in diverse epithelium-derived cell cultures and in myocardial tissue. Immunofluorescence and immunoelectron microscopy allow us to localize PERP predominantly in small intradesmosomal locations and in variously sized, junction-like peri- and interdesmosomal regions ("tessellate junctions"), mostly in mosaic or amalgamated combinations with other molecules believed, to date, to be exclusive components of tight and adherens junctions. In the heart, PERP is a major component of the composite junctions of the intercalated disks connecting cardiomyocytes. Finally, protein PERP is a cobblestone-like general component of special plasma membrane regions such as the bile canaliculi of liver and subapical-to-lateral zones of diverse columnar epithelia and upper urothelial cell layers. We discuss possible organizational and architectonic functions of protein PERP and its potential value as an immunohistochemical diagnostic marker.
    Full-text · Article · May 2013
    • "The first cell–cell adhesion gene identified as a p63 direct target was Perp, which encodes a tetraspan membrane protein that localizes to the desmosomes (47). Perp null mice exhibited frequent basal-suprabasal blistering in the skin and oral cavity (47), and developed ectodermal dysplasia and palmoplantar keratoderma (67). A normal pattern of PERP membrane staining was observed in most AEC patients, although in two unrelated patients PERP expression was reduced in the basal and suprabasal layers of the skin (68), consistent with either reduced PERP expression or with protein delocalization due to alterations of other desmosomal components. "
    [Show abstract] [Hide abstract] ABSTRACT: Ankyloblepharon, ectodermal defects, cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder caused by mutations in the p63 gene, essential for embryonic development of stratified epithelia. The most severe cutaneous manifestation of this disorder is the long-lasting skin fragility associated with severe skin erosions after birth. Using a knock-in mouse model for AEC syndrome we found that skin fragility was associated with microscopic blistering between the basal and suprabasal compartments of the epidermis and reduced desmosomal contacts. Expression of desmosomal cadherins and desmoplakin was strongly reduced in AEC mutant keratinocytes and in newborn epidermis. A similar impairment in desmosome gene expression was observed in human keratinocytes isolated from AEC patients, in p63-depleted keratinocytes and in p63 null embryonic skin, indicating that p63 mutations causative of AEC syndrome have a dominant-negative effect on the wild-type p63 protein. Among the desmosomal components, desmocollin 3, desmoplakin and desmoglein 1 were the most significantly reduced by mutant p63 both at the RNA and protein levels. Chromatin immunoprecipitation experiments and transactivation assays revealed that p63 controls these genes at the transcriptional level. Consistent with reduced desmosome function, AEC mutant and p63-deficient keratinocytes had an impaired ability to withstand mechanical stress, which was alleviated by EGFR inhibitors known to stabilize desmosomes. Our study reveals that p63 is a crucial regulator of a subset of desmosomal genes and that this function is impaired in AEC syndrome. Reduced mechanical strength resulting from p63 mutations can be alleviated pharmacologically by increasing desmosome adhesion with possible therapeutic implications.
    Full-text · Article · Oct 2012
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