Epidermal cell junctions and their regulation by p63 in health and disease

Abstract

As the outermost tissue of the body, the epidermis is the first physical barrier for any pressure, stress or trauma. Several specialized cell-matrix and cell-cell adhesion structures, together with an intracellular network of dedicated intermediate filaments, are required to confer critical resilience to mechanical stress. The transcription factor p63 is a master regulator of gene expression in the epidermis and in other stratified epithelia. It has been extensively demonstrated that p63 positively controls a large number of tissue-specific genes, including those encoding a large fraction of tissue-restricted cell adhesion molecules. Consistent with p63 functions in cell adhesion and in epidermal differentiation, heterozygous mutations clustered mainly in the p63 C-terminus are causative of AEC syndrome, an autosomal dominant disorder characterized by cleft palate, ankyloblepharon and ectodermal dysplasia associated with severe skin erosions, bleeding and infections. The molecular basis of skin erosions in AEC patients is not fully understood, although defects in desmosomes and in other cell junctions are likely to be involved. Here, we provide an extensive review of the different epidermal cell junctions that cooperate to withstand mechanical stress and on the mechanisms by which p63 regulates gene expression of their components in healthy skin and in AEC syndrome. Collectively, advancement in understanding the molecular mechanisms by which epidermal cell junctions precisely exert their functions and how p63 orchestrates their coordinated expression, will ultimately lead to insight into developing future strategies for the treatment of AEC syndrome and more in generally for diseases that share an overlapping phenotype.

ΔNp63α promotes adhesion of metastatic prostate cancer cells to the bone through regulation of CD82

“… 19 , 38 Our findings support these observations, that reactivation of ΔNp63α in a subset of metastatic cells at later stages of colonization might promote mesenchymal–epithelial transition and as we show, adhesion at bone metastatic sites ( Figure 7 ). Indeed, our data adds to the growing body of work linking p63 with adhesion and tumor progression, 27 , 28 , 29 and uncovers an unexpected role for this process in prostate bone metastatic tumor growth.…”

“…Given that cellular adhesion emerged as a major molecular signature in our profiling studies, and the increasing link with p63 and adhesive function in different settings, 27 , 28 , 29 we investigated if this might also be important in prostate bone metastatic cell behavior. First, we checked whether increased expression of ΔNp63α in PC3 cells might confer increased adhesive properties on different ECM substrata ( Figure 4d ).…”

Closing the Gap: Mouse Models to Study Adhesion in Secondary Palatogenesis

“…Although direct evidence for an association between human CP phenotypes and cell adhesion molecules is currently restricted to NECTIN1, CDH1, and EFNB1, there is evidence to suggest that cell adhesions are affected in other OFC syndromes, including those linked to mutant p63 (Ferone et al 2015). p63 (TP63) is a p53 homologue best known as a stratified epithelial-defining transcription factor (Mills et al 1999;Yang et al 1999).…”

Functional and Mechanistic Insights into the Pathogenesis of P63-Associated Disorders

“…The p53 family member p63 is a master regulator of gene expression in stratified epithelia, such as the epidermis. One of the main functions of p63 is to sustain mechanical resistance, positively regulating several epidermal genes involved in cellematrix adhesion and cellecell adhesion (Ferone et al, 2015).…”