Delineating Molecular Mechanisms of Squamous Tissue Homeostasis and Neoplasia: Focus on p63

Abstract

Mouse models have informed us that p63 is critical for normal epidermal development and homeostasis. The p53/p63/p73 family is expressed as multiple protein isoforms due to a combination of alternative promoter usage and C-terminal alternative splicing. These isoforms can mimic or interfere with one another, and their balance ultimately determines biological outcome in a context-dependent manner. While not frequently mutated, p63, and in particular the ΔNp63 subclass, is commonly overexpressed in human squamous cell cancers. In vitro keratinocytes and murine transgenic and transplantation models have been invaluable in elucidating the contribution of altered p63 levels to cancer development, and studies have identified the roles for ΔNp63 isoforms in keratinocyte survival and malignant progression, likely due in part to their transcriptional regulatory function. These findings can be extended to human cancers; for example, the novel recognition of NFκB/c-Rel as a downstream effector of p63 has identified a role for NFκB/c-Rel in human squamous cell cancers. These models will be critical in enhancing the understanding of the specific molecular mechanisms of cancer development and progression.

MiR-223-5p works as an oncomiR in vulvar carcinoma byTP63suppression

“…Similar results have previously been described on the literature [58, 63–65]. Altogether, our results allow us to indicate the loss of p63 as a possible marker of worst prognosis in vulvar cancer.…”

“…In pathology, invasion is characterized as the infiltration of malignant tumor cells into the underlying interstitial tissues [43] and for statistical purposes we divided tumor invasion as compromising superficial/mid dermis or deep dermis/subcutaneous. Molecularly speaking, p63 activates cell-cell adhesiveness through Perp, a tetraspan membrane protein critical for desmosomal adhesion [57, 58]. Decreased p63 expression was demonstrated in the progression of superficial to invasive bladder tumors, but certain invasive tumors sustained widespread p63 expression [59].…”

Intersection of the p63 and NF‐κB pathways in epithelial homeostasis and disease

“…Consistent with this, transcriptome profiling revealed a ΔNp63α‐induced epidermal‐specific gene signature that coincided with the repression of mesodermal gene expression . As the predominant p63 isoform expressed in the epidermis, ΔNp63α is involved in a range of biological functions including proliferation, commitment to stratification, and adhesiveness as well as in apoptosis inhibition and senescence override (reviewed in King 2013) . The critical role played by ΔNp63α in the maintenance of normal epidermal homeostasis was underscored by the inducible knockdown of ΔNp63α postnatally in a mouse model which resulted in a phenotype of severe skin fragility accompanied by erosion that mimicked the phenotype of patients with ankyloblepharon ectodermal dysplasia and clefting (AEC) syndrome, one of a series of ectodermal dysplasia syndromes linked to mutations in the p63 gene (reviewed in Rinne et al 2007) …”

“…p63 is a member of a multigene family that includes p53 and p73. The p63 and p73 were originally identified based on homology to the major functional domains of p53: transactivation (TA), DNA binding (DBD), and oligomerization; all members of this family can present as multiple protein isoforms . p63 exists as two subclasses, TA and ΔNp63, due to the use of alternate gene promoters .…”

Phospho‐ΔNp63α regulates AQP3, ALOX12B, CASP14 and CLDN1 expression through transcription and microRNA modulation

“…TP63 gene encoding proteins with the transactivation domain (TAÀ) and without it (DNÀ) is rarely mutated in cancer, however is often mutated in ectodermal dysplasia [1][2][3][4]. Tp63 null mice display the single-layered and translucent skin, which is unable to prevent water loss [5,6].…”