Roles of p63 in the diethylstilbestrol-induced cervicovaginal adenosis

Women exposed to diethylstilbestrol (DES) in utero develop abnormalities, including cervicovaginal adenosis that can lead to cancer. We report that transient disruption of developmental signals by DES permanently changes expression of p63, thereby altering the developmental fate of Müllerian duct epithelium. The cell fate of Müllerian epithelium to be columnar (uterine) or squamous (cervicovaginal) is determined by mesenchymal induction during the perinatal period. Cervicovaginal mesenchyme induced p63 in Müllerian duct epithelium and subsequent squamous differentiation. In p63(-/-) mice, cervicovaginal epithelium differentiated into uterine epithelium. Thus, p63 is an identity switch for Müllerian duct epithelium to be cervicovaginal versus uterine. P63 was also essential for uterine squamous metaplasia induced by DES-exposure. DES-exposure from postnatal day 1 to 5 inhibited induction of p63 in cervicovaginal epithelium via epithelial ERalpha. The inhibitory effect of DES was transient, and most cervicovaginal epithelial cells recovered expression of p63 by 2 days after discontinuation of DES-treatment. However, some cervicovaginal epithelial cells failed to express p63, remained columnar and persisted into adulthood as adenosis.     

p63在宫颈癌中的研究进展

p63是近年来新发现的p53蛋白家族成员,其在上皮细胞发育,细胞衰老、周期调控与凋亡,癌症的发生、发展中具有重要意义.宫颈癌是影响妇女健康的恶性肿瘤,p63在宫颈癌组织及癌旁组织的差异表达,提示其在宫颈癌中具有非同寻常的作用.介绍了p63蛋白的结构与功能,阐述了在宫颈癌细胞中p63与HPV瘤蛋白E6以及p63与NF-κB信号通路中相关蛋白相互作用关系的研究进展.     

Splitting p63

Causative TP63 mutations have been identified in five distinct human developmental disorders that are characterized by various degrees of limb abnormalities, ectodermal dysplasia, and facial clefts. The distribution of mutations over the various p63 protein domains and the structural and functional implications of these mutations establish a clear genotype-phenotype correlation.     

p63基因的结构与功能

p63基因是肿瘤抑制基因p53家族成员之一,与p53基因表现出高度同源性.较之p53基因,p63基因更为复杂.p63的两个不同启动子和多种内含子剪接方式,导致p63基因编码产生多种亚型P63蛋白.这些P63亚型蛋白,在不同的组织不同的发育阶段发挥不同的生物学功能.本文就p63基因结构、p63在细胞周期和凋亡中的作用,以及在表皮发育中的功能等方面的研究进展作一概述.     

p63 Immunoexpression in lip carcinogenesis

Actinic cheilitis (AC) is a potentially malignant disorder, which can present degrees of epithelial dysplasia, and may even evolve into lip squamous cell carcinoma (LSCC). Since p63 is a protein homologous to p53, which can be associated with tumorigenesis in epithelial tissues, this study aims to evaluate it in AC and LSCC, in the hopes to estimate the biological behavior of these lesions. Forty AC lesions and sixty-five cases of LSCC were quantitatively analyzed by immunohistochemistry, using anti-p63 antibody with ten cases of normal lip mucosa used as a control group. In all AC and LSCC cases studied, it was possible to detect the presence of the p63 protein. There was no statistically significant difference between immunostained cells and degree of epithelial dysplasias, nor between the LSCC grading malignancy. Nevertheless, p63 immunoexpression showed to be significantly correlated with AC and LSCC lesions as compared to normal lip epithelium. The results indicate that p63 protein is consistently expressed in AC and LSCC, and might be of help in the differential diagnosis between normal and dysplastic/neoplastic epithelium, although the evaluation using a primary antibody to all isotypes did not prove to be a risk biomarker during lip carcinogenesis. Thus, the production of antibodies for the six different p63 isotypes is urged, since in isolation they can have predictive value, mainly the ΔNp63 isoforms.     

From p63 to p53 across p73

Most genes are members of a family. It is generally believed that a gene family derives from an ancestral gene by duplication and divergence. The tumor suppressor p53 was a striking exception to this established rule. However, two new p53 homologs, p63 and p73, have recently been described [1, 2, 3, 4, 5 and 6]. At the sequence level, p63 and p73 are more similar to each other than each is to p53, suggesting the possibility that the ancestral gene is a gene resembling p63/p73, while p53 is phylogenetically younger [1 and 2].

The complexity of the family has also been enriched by the alternatively spliced forms of p63 and p73, which give rise to a complex network of proteins involved in the control of cell proliferation, apoptosis and development [1, 2, 4, 7, 8 and 9].

In this review we will mainly focus on similarities and differences as well as relationships among p63, p73 and p53.     

Differential effects of p63 mutants on transactivation of p53 and/or p63 responsive genes

p63, known to play a role in development, has more recently also been implicated in cancer progression. Mutations in p63 have been shown to be responsible for several human developmental diseases. Differential splicing of the p63 gene gives rise to p63 isoforms, which can act either as tumor suppressors or as oncogene. In this report, we studied the effects of naturally occurring TAp637 mutants on the regulation of p53/p63 and p63 specific target genes. We observed significant differences among p63 mutants to regulate the p53/p63 and p63 specific target genes. Additionally, we observed a differential effect of p63 mutants on wildtype-p63-mediated induction ofp53/p63 and p63 specific target genes. We also demonstrated that these mutants differentially regulate the binding of wildtype p63 to the promoter of target genes. Furthermore, the effects of these mutants on cell death and survival were consistent with their ability to regulate the downstream targets when compared to wildtype TAp63T. In summary, our data demonstrate that p63 mutants exhibit differential effects on p63 and p53/p63 specific target genes and on the induction of apoptosis, and provide further insight into the function of p63.     

Role of p63 in cancer development

Since their initial identification p53 homologues p63 and p73 have been expected to play a role in cancer development due to their close homology to p53, notoriously one of the most mutated genes in cancer. However soon after their discovery the awareness that these genes were rarely mutated in cancer seemed to indicate that they did not play a role in its development. However a large number of data collected in the following years indicated that altered expression rather than mutation could be found in different neoplasia and play a role in its biology. In particular p63 due to its fundamental role in epithelial development seems to play a role in a number of tumors of epithelial origin. In this review we summarize some of the evidence linking p63 to carcinogenesis.     

p63 regulation by microRNAs

Wafik S. El-Deiry, M.D., Ph.D., American Cancer Society Research Professor at the University of Pennsylvania, organized and hosted in Philadelphia the 199th Meeting of the Interurban Clinical Club (interurbanclinicalclub.org) started by Sir William Osler in 1905. The Scientific Meeting was held at the College of Physicians of Philadelphia and featured outstanding presentations of the most exciting biomedical research in Philadelphia. The evening black-tie dinner event was held at the historic Union League of Philadelphia where Margaret Foti, Ph.D., M.D. (h.c.), Chief Executive Officer of the American Association for Cancer Research addressed the attendees.     

Neurodevelopment on route p63

All known members of the p53 gene family, including the two homologs p73 and p63, have multiple biological functions. In neurons, p53 and p73 are known to regulate cell death in the developing and adult nervous system. A report by Jacobs et al. in this issue of Neuron shows that the more ancestral member of this gene family, p63, is an essential proapoptotic protein during neuronal development.     

Degradation of p63 by Itch

No abstract available.