p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome

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 epidermal growth factor receptor 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.

mTORC1 loss impairs epidermal adhesion via TGF-β/Rho kinase activation

“…Overall, however, the uniform decrease in most protein levels, including DSP1/2 and PKP3, which are expressed by keratinocytes throughout differentiation (Supplemental Figure 2B and see below), suggested that the failure of desmosome protein expression in keratinocytes with mTORC1 loss of function was at least partly independent of cellular differentiation. Desmosomal protein expression is regulated at multiple levels, including at the level of gene expression as well as by protein turnover (49). We examined mRNA expression for desmosomal genes in both cKO models.…”

Desmocollin-3 and Cancer

“…Mutant p53 inactivates p63 and is also associated with down regulation of DSC3 [10]. p63 is a master regulator of epidermal gene transcription and plays an essential function in controlling epidermal development , cell proliferation, stratification and cell-matrix adhesion [13]. There are two main isoforms of p63, Tap63 and Delta Np63.…”

“…Delta Np63 alpha isoform is the most abundantly expressed p63 isoform. Both p63 and delta Np63 are activator for desmocollin-3 gene [13]. Knockdown of p63 and delta Np63 results in marked reduction in expression of DSC3 without any effect on expression of another adhesion molecule E-cadherin [13].…”

Multifocal epithelial tumors and field cancerization: stroma as a primary determinant

“…Cell populations with p53 mutations in apparently normal tissues have also been found in a number of other organs, including oral (43,44), bronchial (45,46), bladder (35), and esophageal (32,47) epithelium. In concert with p53, its cousin p63 is also involved in epithelial stem cell potential and/or cell-cell adhesion (48)(49)(50). The functional implications of loss of normal p53 and/or altered p53/ p63 balance seem obvious; however, the possibility that p53 mutations can be a marker of expanding clones of cells, rather than an initial or obligate cancer-triggering event, should also be considered.…”