Disease relevance of Trp63

• In contrast, p63 protein is not detected in human prostate adenocarcinomas [1].
• Furthermore, p63+/- mice were not prone to chemically induced tumorigenesis, and p63 expression was maintained in carcinomas [2].
• P63 was also essential for uterine squamous metaplasia induced by DES-exposure [3].
• Mice lacking the p53/p63 target gene Perp are resistant to papilloma development [4].
• Defects in the first pathway explain imperforate anus, vaginal septum, genital hypoplasia, and micropenis reported in humans with p63 mutations [5].

Psychiatry related information on Trp63

• Finally, to better evaluate the potential role of p63 in human development of DES-induced cervical/vaginal adenosis, we describe the ontogeny of p63 in human female fetuses [6].

High impact information on Trp63

• Perp is a p63-regulated gene essential for epithelial integrity [7].
• We show here that Perp, a tetraspan membrane protein originally identified as an apoptosis-associated target of the p53 tumor suppressor, is the first direct target of p63 clearly involved in mediating this developmental program in vivo [7].
• During embryogenesis, Perp is expressed in an epithelial pattern, and its expression depends on p63 [7].
• p63 is a p53 homologue required for limb and epidermal morphogenesis [8].
• Here we report that mice homozygous for a disrupted p63 gene have major defects in their limb, craniofacial and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches and epidermal appendages, which are all sites of reciprocal signalling that direct morphogenetic patterning of the underlying mesoderm [9].

Biological context of Trp63

• These findings demonstrate that Perp is a key effector in the p63 developmental program, playing an essential role in an adhesion subprogram central to epithelial integrity and homeostasis [7].
• Importantly, the predominant p63 isotypes in many epithelial tissues lack an acidic N terminus corresponding to the transactivation domain of p53 [10].
• Overexpression of TAp63 causes neuronal apoptosis in the presence of NGF, while cultured p63-/- neurons are resistant to apoptosis following NGF withdrawal [11].
• The epidermal phenotype was reminiscent of defects seen in p63(-/-) mice [12].
• Consistent with this, reduced p63 expression was observed in transgenic offspring expressing either RAR mutant, suggesting that down-regulation of p63 might underlie the effects of these receptors on epidermal development [12].

Anatomical context of Trp63

• Another novel finding reported in this study is the fact that p63(-/-) mice develop a bladder mucosa epithelial layer yet fail to complete uroepithelial differentiation, producing a nontransitional default cuboidal epithelium [13].
• These results indicate that p63 is required for prostate development and support the hypothesis that basal cells represent and/or include prostate stem cells [1].
• It has been previously shown that p63 is expressed in normal urothelium [13].
• Mouse embryo fibroblasts derived from deltaEF1-deficient mice exhibit unbalanced expression of DeltaNp63, TAp73 and DeltaNp73 but not of TAp63 and p53 [14].
• Interestingly, TAp63 variants, which include the conserved transactivation domain TA at their amino-terminus, were also expressed in wound keratinocytes as well as at the edge of the injured subcutaneous muscle panniculus carnosus [15].

Associations of Trp63 with chemical compounds

• Conversely, TAp63 transcribed the upper layer's genes (Ets-1, K1, transglutaminases, involucrin) [16].
• Prostatic tissue that developed in p63(-/-) UGS grafts contained neuroendocrine and luminal cells, but basal cells were absent [17].
• Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis [3].
• However, regressed p63(-/-) prostate did regenerate in response to androgen administration, indicating that basal cells were not essential for prostatic regeneration [17].
• In the human fetus at the susceptible stage for DES-induced cervical/vaginal adenosis, most cervical/vaginal epithelial cells were columnar and negative for p63 [6].

Physical interactions of Trp63

• Additional demonstration with known p53 response elements suggested that DNA-binding profiles of p51A and p73L were very similar but were distinct from that of p53 [18].

Co-localisations of Trp63

• Moreover, p63 expression in tooth seems not to be fully colocalized with nuclear Ki67 expression [19].

Regulatory relationships of Trp63

• Immunofluorescence analysis reveals a complete co-localization of HMGN1 and p 63 in small clusters of basal corneal epithelial cells of wild-type mice, and an absence of p 63 expressing cells in the central region of the Hmgn1(-/-) cornea [20].

Other interactions of Trp63

• One mechanism for this gain-of-function potential is the inhibition of function of the p53 family members p63 and p73 [21].
• Here, we show p63 expression during teeth and vibrissae morphogenesis in mouse embryos and we also show a correlation with the expression patterns of the epithelial marker keratin 5 and the proliferation marker Ki67 [19].
• Furthermore, we found that Notch1 expression following castration and hormone replacement was concomitant with known basal cell markers p63 and cytokeratin 14 and was high in the proliferative human prostate epithelial cells [22].
• Importantly, our urogenital sinus transplantation studies demonstrate that p63 prevents intestinal differentiation of the urogenital sinus endoderm and is therefore required to maintain commitment to the prostate cell lineage [23].
• DES-exposure from postnatal day 1 to 5 inhibited induction of p63 in cervicovaginal epithelium via epithelial ERalpha [3].
• ChIP analysis shows that p63 is directly associated with the Dlx5 and Dlx6 promoters [24].

Analytical, diagnostic and therapeutic context of Trp63

• Furthermore, our results show that p63 immunohistochemistry may be a valuable tool in the differential diagnosis of benign versus malignant prostatic lesions [1].
• Using the GeneBridge 4 radiation hybrid panel, we have mapped KET to human Chromosome (Chr) 3q27 [25].
• One gene (Trp63) was identified whose expression was upregulated by all four genotoxic substances regardless of the presence or absence of carcinogenicity; this finding, however, was not confirmed by quantitative real-time RT-PCR [26].
• By using oligonucleotide expression microarray analysis and analyzing the promoters of p63-induced genes, we have identified novel p63-specific response elements (p63-REs) in the promoter regions of EVPL and SMARCD3 [27].
• In the response to castration, regression of p63(-/-) prostate was inordinately severe with almost complete loss of ducts, resulting in the formation of residual cystic structures devoid of epithelium [17].

References