P63 modulates the expression of the WDFY2 gene which is implicated in cancer regulation and limb development.
Carcinogenesis
/ genetics
DNA-Binding Proteins
/ genetics
Gene Expression Regulation, Neoplastic
/ genetics
Humans
Intracellular Signaling Peptides and Proteins
/ genetics
Neoplasms
/ genetics
Protein Isoforms
/ genetics
Response Elements
/ genetics
Signal Transduction
/ genetics
Transcription Factors
/ genetics
Transcriptional Activation
/ genetics
Tumor Suppressor Protein p53
/ genetics
Tumor Suppressor Proteins
/ genetics
P63
WDFY2
cancer regulation
functional analysis
limb development
target gene
Journal
Bioscience reports
ISSN: 1573-4935
Titre abrégé: Biosci Rep
Pays: England
ID NLM: 8102797
Informations de publication
Date de publication:
20 12 2019
20 12 2019
Historique:
received:
20
06
2019
revised:
15
11
2019
accepted:
29
11
2019
pubmed:
4
12
2019
medline:
26
9
2020
entrez:
3
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31789342
pii: 221381
doi: 10.1042/BSR20192114
pmc: PMC6914664
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Intracellular Signaling Peptides and Proteins
0
Protein Isoforms
0
TP63 protein, human
0
Transcription Factors
0
Tumor Suppressor Protein p53
0
Tumor Suppressor Proteins
0
WDFY2 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2019 The Author(s).
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