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The p63 gene encodes amaster regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the C-terminal domain of the p63 gene can cause ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility and severe, long-lasting skin erosions. Despite deep knowledge of p63 functions, little is known about mechanisms underlying disease pathology and possible treatments. Here, we show that multiple AEC-associated p63 mutations, but not those causative of other diseases, lead to thermodynamic protein destabilization, misfolding, and aggregation, similar to the known p53 gain-of-function mutants found in cancer. AEC mutant proteins exhibit impaired DNA binding and transcriptional activity, leading to dominant negative effects due to coaggregation with wild-type p63 and p73. Importantly, p63 aggregation occurs also in a conditional knock-in mouse model for the disorder, in which the misfolded p63 mutant protein leads to severe epidermal defects. Variants of p63 that abolish aggregation of the mutant proteins are able to rescue p63’s transcriptional function in reporter assays as well as in a human fibroblast-to-keratinocyte conversion assay. Our studies reveal that AEC syndrome is a protein aggregation disorder and opens avenues for therapeutic intervention.

Background: The latest immunotherapy, used in the treatment of non-small cell lung cancer (NSCLC), uses monoclonal antibodies directed against programmed death ligand 1 (PD-L1) to inhibit its interaction with the PD-1 receptor. Elevated levels of PD-L1 expression were observed on NSCLC cells. The association between PD-L1 expression and clinicopathological features is still unclear. Therefore, we examined this relationship and also compare PD-L1 expression levels with Ki-67, p63 and TTF-1. Methods: 866 samples of NSCLCs were used to prepare tissue microarrays (TMAs) on which immunohistochemical (IHC) reactions were performed. Changes in the level of CD274 (PD-L1) gene expression in 62 NSCLC tumors were tested in relation to 14 normal lung tissues by real-time PCR reactions (RT-PCR). Results: PD-L1 expression was observed in 32.6% of NSCLCs. PD-L1 expression was increased in higher malignancy grades (G) (p < 0.0001) and in higher lymph node status (pN) (p = 0.0428). The patients with low PD-L1 expression had longer overall survival compared to the group with high expression (p = 0.0332) in adenocarcinoma (AC) only. Conclusions: PD-L1 expression seems to be associated with increased tumor proliferation and aggressiveness as well as shorter patient survival in NSCLC, predominantly in the AC group.

Poorly differentiated squamous cell carcinoma (PDSCC) is an aggressive oral malignancy with rapid progression, high recurrence, and poor survival. This study aimed to evaluate the clinicopathological features, immunohistochemical expression of p63 and EGFR, and quality of life (QOL) in PDSCC compared to well-differentiated SCC (WDSCC). In this retrospective observational study, 78 histopathologically confirmed OSCC cases (39 PDSCC and 39 WDSCC) from 2019-2025 were analyzed. Histopathological parameters including tumor size, depth of invasion, perineural and lympho-vascular invasion, were recorded. Immunohistochemistry was performed on representative samples using p63 and EGFR. QOL was assessed using EORTC QLQ-C30 and QLQ-H&N43. Statistical analysis was performed using Chi-square/Fisher's exact test and Mann-Whitney U test; survival was assessed using Kaplan-Meier and Log-rank test. Bonferroni correction was applied, with significance set at p < 0.001. PDSCC showed shorter lesion duration compared to WDSCC. Significant differences were observed in anatomical site distribution, mitotic activity, and keratin pearl formation, reflecting the higher aggressiveness of PDSCC. Immunohistochemistry revealed reduced p63 and aberrant EGFR expression, though differences were not statistically significant. QOL was comparatively lower in PDSCC. Survival analysis confirmed inferior outcomes in PDSCC (mean survival 1.27 years) versus WDSCC (3.28 years, p < 0.001). PDSCC exhibits aggressive pathology and compromised QOL, underscoring the need for early recognition and biomarker-based prognostication.

Thirty-five years of research on p53 gave rise to more than 68,000 articles and reviews, but did not allow the uncovering of all the mysteries that this major tumor suppressor holds. How p53 handles the different signals to decide the appropriate cell fate in response to a stress and its implication in tumorigenesis and cancer progression remains unclear. Nevertheless, the uncovering of p53 isoforms has opened new perspectives in the cancer research field. Indeed, the human TP53 gene encodes not only one but at least twelve p53 protein isoforms, which are produced in normal tissues through alternative initiation of translation, usage of alternative promoters, and alternative splicing. In recent years, it became obvious that the different p53 isoforms play an important role in regulating cell fate in response to different stresses in normal cells by differentially regulating gene expression. In cancer cells, abnormal expression of p53 isoforms contributes actively to cancer formation and progression, regardless of TP53 mutation status. They can also be associated with response to treatment, depending on the cell context. The determination of p53 isoform expression and p53 mutation status helps to define different subtypes within a particular cancer type, which would have different responses to treatment. Thus, the understanding of the regulation of p53 isoform expression and their biological activities in relation to the cellular context would constitute an important step toward the improvement of the diagnostic, prognostic, and predictive values of p53 in cancer treatment. This review aims to summarize the involvement of p53 isoforms in cancer and to highlight novel potential therapeutic targets.

Metformin has been used as therapy for type 2 diabetes for many years. Clinical and basic evidence as indicated that metformin has anti-cancer activities. It has been well-established that metformin activates AMP-activated protein kinase (AMPK), which in turn regulates energy homeostasis. However, the mechanistic aspects of metformin anti-cancer activity remain elusive. p53 family proteins, including p53, p63 and p73, have diverse biological functions, including regulation of cell growth, survival, development, senescence and aging. In this review, we highlight the evidence and mechanisms by which metformin inhibits cancer cell survival and tumor growth. We also aimed to discuss the role of p53 family proteins in metformin-mediated suppression of cancer growth and survival.

Purpose This review will discuss the role of vitamin D and calcium signaling in the epidermal wound response with particular focus on the stem cells of the epidermis and hair follicle that contribute to the wounding response. Methods Selected publications relevant to the mechanisms of wound healing in general and the roles of calcium and vitamin D in wound healing in particular were reviewed. Results Following wounding the stem cells of the hair follicle and interfollicular epidermis are activated to proliferate and migrate to the wound where they take on an epidermal fate to re-epithelialize the wound and regenerate the epidermis. The vitamin D and calcium sensing receptors (VDR and CaSR, respectively) are expressed in the stem cells of the hair follicle and epidermis where they play a critical role in enabling the stem cells to respond to wounding. Deletion of Vdr and/or Casr from these cells delays wound healing. The VDR is regulated by co-regulators such as the Med 1 complex and other transcription factors such as Ctnnb (beta-catenin) and p63. The formation of the Cdh1/Ctnn (E-cadherin/catenin) complex jointly stimulated by vitamin D and calcium plays a critical role in the activation, migration, and re-epithelialization processes. Conclusion Vitamin D and calcium signaling are critical for the ability of epidermal and hair follicle stem cells to respond to wounding. Vitamin D deficiency with the accompanying decrease in calcium signaling can result in delayed and/or chronic wounds, a major cause of morbidity, loss of productivity, and medical expense.

Signal Transducer and Activator of Transcription 3 (STAT3) is a transcription factor with many important functions in the biology of normal and transformed cells. Its regulation is highly complex as it is involved in signaling pathways in many different cell types and under a wide variety of conditions. Besides other functions, STAT3 is an important regulator of normal stem cells and cancer stem cells. p63 which is a member of the p53 protein family is also involved in these functions and is both physically and functionally connected with STAT3. This review summarizes STAT3 function and regulation, its role in stem cell and cancer stem cell properties and highlights recent reports about its relationship to p63.

Ankyloblepharon‐ectodermal defects‐cleft lip/palate (AEC) syndrome, which is characterized by cleft palate and severe defects of the skin, is an autosomal dominant disorder caused by mutations in the gene encoding transcription factor p63. Here, we report the generation of a knock‐in mouse model for AEC syndrome ( p63 +/L514F ) that recapitulates the human disorder. The AEC mutation exerts a selective dominant‐negative function on wild‐type p63 by affecting progenitor cell expansion during ectodermal development leading to a defective epidermal stem cell compartment. These phenotypes are associated with impairment of fibroblast growth factor (FGF) signalling resulting from reduced expression of Fgfr2 and Fgfr3 , direct p63 target genes. In parallel, a defective stem cell compartment is observed in humans affected by AEC syndrome and in Fgfr2b −/− mice. Restoring Fgfr2b expression in p63 +/L514F epithelial cells by treatment with FGF7 reactivates downstream mitogen‐activated protein kinase signalling and cell proliferation. These findings establish a functional link between FGF signalling and p63 in the expansion of epithelial progenitor cells and provide mechanistic insights into the pathogenesis of AEC syndrome. See accompanying article http://dx.doi.org/10.1002/emmm.201100202

Background: p63 is a transcription factor with intrinsic pioneer factor activity and pleiotropic functions. Transforming growth factor beta (TGF beta) signaling via activation and cooperative action of canonical, SMAD, and non-canonical, MAP-kinase (MAPK) pathways, elicits both anti- and pro-tumorigenic properties, including cell stemness and invasiveness. TGF beta activates the Delta Np63 transcriptional program in cancer cells; however, the link between TGF beta and p63 in unmasking the epigenetic landscape during tumor progression allowing chromatin accessibility and gene transcription, is not yet reported. Methods: Small molecule inhibitors, including protein kinase inhibitors and RNA-silencing, provided loss of function analyses. Sphere formation assays in cancer cells, chromatin immunoprecipitation and mRNA expression assays were utilized in order to gain mechanistic evidence. Mass spectrometry analysis coupled to co-immunoprecipitation assays revealed novel p63 interactors and their involvement in p63-dependent transcription. Results: The sphere-forming capacity of breast cancer cells was enhanced upon TGF beta stimulation and significantly decreased upon Delta Np63 depletion. Activation of TGF beta signaling via p38 MAPK signaling induced Delta Np63 phosphorylation at Ser 66/68 resulting in stabilized Delta Np63 protein with enhanced DNA binding properties. TGF beta stimulation altered the ratio of H3K27ac and H3K27me3 histone modification marks, pointing towards higher H3K27ac and increased p300 acetyltransferase recruitment to chromatin. By silencing the expression of Delta Np63, the TGF beta effect on chromatin remodeling was abrogated. Inhibition of H3K27me3, revealed the important role of TGF beta as the upstream signal for guiding Delta Np63 to the TGF beta/SMAD gene loci, as well as the indispensable role of Delta Np63 in recruiting histone modifying enzymes, such as p300, to these genomic regions, regulating chromatin accessibility and gene transcription. Mechanistically, TGF beta through SMAD activation induced dissociation of Delta Np63 from NURD or NCOR/SMRT histone deacetylation complexes, while promoted the assembly of Delta Np63-p300 complexes, affecting the levels of histone acetylation and the outcome of Delta Np63-dependent transcription. Conclusions: Delta Np63, phosphorylated and recruited by TGF beta to the TGF beta/SMAD/Delta Np63 gene loci, promotes chromatin accessibility and transcription of target genes related to stemness and cell invasion.

Immunohistochemistry has recently emerged as a powerful ancillary tool for differentiating lung adenocarcinoma and squamous cell carcinoma—a distinction with important therapeutic implications. Although the most frequently recommended squamous marker p63 is extremely sensitive, it suffers from low specificity due to its reactivity in a substantial proportion of lung adenocarcinomas and other tumor types, particularly lymphomas. p40 is a relatively unknown antibody that recognizes ΔNp63—a p63 isoform suggested to be highly specific for squamous/basal cells. Here we compared the standard p63 antibody (4A4) and p40 in a series of 470 tumors from the archives of Memorial Sloan–Kettering Cancer Center and The Johns Hopkins Hospital, which included lung squamous cell carcinomas ( n =81), adenocarcinomas ( n =237), and large cell lymphomas ( n =152). The p63 was positive in 100% of squamous cell carcinomas, 31% of adenocarcinomas, and 54% of large cell lymphomas (sensitivity 100%, specificity 60%). In contrast, although p40 was also positive in 100% of squamous cell carcinomas, only 3% of adenocarcinomas, and none of large cell lymphomas had p40 labeling (sensitivity 100%, specificity 98%). The mean percentage of p63 versus p40-immunoreactive cells in squamous cell carcinomas was equivalent (97 vs 96%, respectively, P =0.73). Rare adenocarcinomas with p40 labeling had reactivity in no more than 5% of tumor cells, whereas the mean (range) of p63-positive cells in adenocarcinomas and lymphomas was 26% (1–90%) and 48% (2–100%), respectively. In summary, p40 is equivalent to p63 in sensitivity for squamous cell carcinoma, but it is markedly superior to p63 in specificity, which eliminates a potential pitfall of misinterpreting a p63-positive adenocarcinoma or unsuspected lymphoma as squamous cell carcinoma. These findings strongly support the routine use of p40 in place of p63 for the diagnosis of pulmonary squamous cell carcinoma.