P63 modulates the expression of theWDFY2gene which is implicated in cancer regulation and limb development

Abstract

TP63 is a member of the TP53 gene family, sharing a common gene structure that produces two groups of mRNAs’ encoding proteins with different N-terminal regions (ΔN and TA isoforms); both transcripts are also subjected to alternative splicing mechanisms at C-terminus, generating a variety of isoforms. p63 is a master regulator of epidermal development and homoeostasis as well as an important player in tumorigenesis and cancer progression with both oncogenic and tumour suppressive roles. A number of studies have aimed at the identification of p63 target genes, allowing the dissection of the molecular pathways orchestrated by the different isoforms. In the present study we investigated in more detail the p63 responsiveness of the WDFY2 (WD repeat and FYVE domain containing 2) gene, encoding for an endosomal protein identified as a binding partner of the PI-3K/AKT signalling pathway. We showed that overexpression of different p63 isoforms was able to induce WDFY2 expression in TP53-null cells. The p63-dependent transcriptional activation was associated with specific response elements (REs) that have been identified by a bioinformatics tool and validated by yeast- and mammal-based assays. Interestingly, to confirm that WDFY2 belongs to the p63 network of cancer regulation, we analysed the impact of WDFY2 alterations, by showing its frequent deletion in different types of tumours and suggesting its expression level as a prognostic biomarker. Lastly, we identified a chromosomal translocation involving the WDFY2 locus in a patient affected by a rare congenital limb anomaly, indicating WDFY2 as a possible susceptibility gene placed downstream p63 in the network of limb development.

Distinct p63 and p73 Protein Interactions Predict Specific Functions in mRNA Splicing and Polyploidy Control in Epithelia

“…The DNp63 [ 146 , 147 , 148 ] as well as alternative splicing [ 149 ] and polyadenylation [ 150 ] play a major role in keratinocytes differentiation and in cancerogenesis [ 151 ].…”

Comprehensive Characterization of the Coding and Non-coding Single Nucleotide Polymorphisms in the Tumor Protein p63 (TP63) Gene Using In Silico Tools.

“…It has been observed from the study that all nsSNPs did not have a signi cant deleterious impact on protein activity-many SNPs are either deleterious or pathogenic, some are neutral or show insigni cant in uence. It is critical to (1) to evaluate the vulnerability of particular SNPs to pathogens and (2) to emphasize on SNPs which are accountable for systemic and functional effects on proteins i.e.TP63. Moreover, the use of a single bioinformatic tool for predicting the pathogenic effect of nsSNPs is not trustworthy or reliable as screening with single tool may result in unsatisfactory outcome with low con dence 43 .…”

“…It has 12 isoforms listed in UniProt database.TP63 isoform1 gene encodes TP63) protein of 680 amino acid long. TP63 gene encodes for a transcription factor (TF) that regulates gene expressions in multiple pathways, notably in tumorigenesis and development 1 .TP63 protein functions as a transcriptional activator or repressor which binds to DNA in a sequencespeci c manner 2 and shares sequence similarity with the tumor suppressor p53 family. Mutations in TP63 are known to cause ectodermal dysplasia in humans.…”

“…Therefore, the present study was aimed to determine various nsSNPs of the human TP63 gene using SIFT, CADD, PROVEAN, PolyPhen2, PANTHER, PhD-SNP, SNP&GO, I-Mutant 2.0, ClinVar, Mutpred2, ConSurf, HOPE, and Mutation 3D. In addition, we also decided to (1) detect the effect of nsSNPs on binding a nity with ligand by molecular docking using PyRx, Haddock, Chimera 1.14, (2) Visualize the effects of nsSNPs using Swiss PDB Viewer, and (3) analyze noncoding SNPs in TP63 gene through RegulomeDB, PolymiRTS, and GTEx portal analysis (Figure 1).…”

Comprehensive Characterization of the Coding and Non-Coding Single Nucleotide Polymorphisms in the Tumor Protein p63 (TP63) Gene Using In Silico Tools

“…It has 12 isoforms listed in the UniProt database. TP63 isoform 1 is 680 amino acids long and acts as a transcription factor (TF) that regulates gene expressions in multiple pathways, notably in tumorigenesis and development [ 1 ]. TP63 plays an essential role in the development of the body’s organs and tissues.…”