| 1998 |
TP63 (p73L/KET) encodes a protein with a DNA-binding domain sharing 60.6% identity with p53 and 87.8% identity with p73, placing it as a second p53-related family member; Northern blot analysis showed distinct expression profiles from p73, implying separate tissue-specific roles. |
Molecular cloning, chromosomal mapping (in situ hybridization), Northern blot analysis |
Biochemical and biophysical research communications |
Medium |
9703973
|
| 1998 |
Human KET (TP63) maps to chromosome 3q27 between SST and APOD, encodes a 680-amino-acid protein sharing 98% identity with the rat homolog, and is expressed in a pattern consistent with roles in development and differentiation. |
cDNA cloning, radiation hybrid panel mapping, sequence analysis |
Mammalian genome |
Medium |
9799841
|
| 2001 |
Multiple KET/p63 splice variants exist; transactivation of the p53-responsive p21 promoter inversely correlated with the length of the N-terminal domain. The amino-terminally truncated ΔNKETα isoform is expressed in epithelial tissues, while the most p53-like isoform TAKETγ is detected in skeletal muscle. |
RT-PCR cloning of splice variants, luciferase reporter transactivation assay, tissue Northern/RT-PCR analysis |
FEBS letters |
Medium |
11470269
|
| 2001 |
A novel isoform ΔNp73L (ΔNp63) is predominantly expressed in squamous cell carcinomas and can inhibit p53- and p51 (TAp63)-mediated transactivation in co-transfection assays, acting as a dominant-negative inhibitor. |
RT-PCR expression profiling, transient co-transfection reporter assay |
British journal of cancer |
Medium |
11336476
|
| 2003 |
An AEC/Rapp-Hodgkin syndrome missense mutation R279H in the TP63 DNA-binding domain disrupts the dominant-negative activity of ΔNp63α and γ isoforms on TP53 transcriptional activity, establishing a functional mechanism for the syndrome. |
Functional analysis of TP63 mutant isoforms, luciferase reporter assay |
European journal of human genetics |
Medium |
12939657
|
| 2007 |
TP63 (TAp63 isoforms) transcriptionally activates the MFGE8 (MFG-E8/lactadherin) gene through a p53/p63 response element at –370 bp upstream of the MFGE8 promoter; ΔNp63 enhances this activation when dominant over TAp63 (as in undifferentiated keratinocytes/SCCs). siRNA silencing of p63 in SCC cells decreased MFG-E8 production and reduced Saos-2 cell adhesion. |
Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, tetracycline-inducible expression system, immunohistochemistry |
Oncogene |
High |
17637751
|
| 2008 |
In Tp63-deficient mice, facial clefting results from increased Bmp4 signaling in facial process epithelia, which antagonistically reduces Fgf8 and Shh signaling, leading to reduced mesenchymal cell proliferation and increased cell death; thus Tp63 regulates Bmp4 signaling to control facial morphogenesis. |
Analysis of Tp63 knockout mouse model, signaling molecule expression analysis (Bmp4, Fgf8, Shh), cell proliferation and death assays |
Developmental biology |
High |
18634775
|
| 2008 |
Reciprocal regulatory interactions exist between hedgehog signaling and TP63 in mammary stem/progenitor cells: ΔNp63 and TAp63 are segregated between mammary stem and progenitor fractions respectively; Indian Hedgehog is a binary transcriptional target of TP63; hedgehog signaling promotes differential TP63 promoter usage via disruption of Gli3/Gli3R accumulation, and shRNA knockdown of Gli3 altered TP63 promoter usage and enhanced mammary stem cell clonogenicity. |
shRNA knockdown, in vivo hedgehog activation, flow cytometry fractionation, promoter usage analysis |
Stem cells |
Medium |
18292212
|
| 2009 |
AEC-syndrome-associated TP63 SAM-domain mutants differentially impair transcriptional induction of the desmosomal protein PERP (a TP63 target critical for cell-cell adhesion), with some but not all AEC mutants showing compromised PERP induction in luciferase reporter assays; skin biopsies from a subset of AEC patients showed aberrant PERP expression. |
Luciferase reporter assay with AEC TP63 mutants, immunohistochemistry of patient skin biopsies |
American journal of medical genetics. Part A |
Medium |
19353588
|
| 2010 |
Upon cisplatin treatment, ATM-dependent phosphorylation of ΔNp63α activates it as a transcription factor that binds the RPN13 promoter via a TP63-responsive element, recruits DDIT3 (CHOP), NF-Y, and NF-κB as co-factors, and induces RPN13 transcription, leading to NOS2 degradation; siRNA knockdown of RPN13 rescued NOS2 from cisplatin-dependent inactivation. |
Chromatin immunoprecipitation, reporter assay, siRNA knockdown, Western blot |
The Journal of biological chemistry |
High |
20959455
|
| 2011 |
ΔNp63α expression is regulated by the Wnt/β-catenin pathway through TCF/LEF binding sites in the TP63 P2 promoter; β-catenin and ΔNp63 are co-expressed in esophageal SCC, and activation of this pathway contributes to ΔNp63 overexpression in cancer. |
Luciferase reporter assay, promoter mutation analysis, immunohistochemistry |
Oncogene |
Medium |
21643019
|
| 2012 |
AEC-syndrome-causing TP63 mutants impair epidermal differentiation by downregulating ZNF750 and other differentiation activators; ChIP and ChIP-seq demonstrated that wild-type and AEC mutant TP63 directly binds the ZNF750 locus; restoring ZNF750 in AEC organotypic tissue rescued differentiation, establishing ZNF750 as an essential downstream target. |
ChIP, ChIP-seq, organotypic human epidermal tissue with AEC TP63 mutants, gene rescue experiment |
American journal of human genetics |
High |
22922031
|
| 2013 |
ΔNp63α activates transcription of SUFU (a negative regulator of hedgehog signaling) in keratinocytes, thereby lowering HH pathway activity during differentiation. Loss of SUFU caused deregulation of keratinocyte differentiation and BCL2 overexpression. In vivo murine models also showed GLI-mediated regulation of the TP63 pathway, establishing a reciprocal regulatory node. |
In vitro reporter assay, in vivo murine models, loss-of-function keratinocyte differentiation assays |
Cell death and differentiation |
Medium |
23686138
|
| 2013 |
EEC and ADULT syndrome TP63 mutations in the DNA-binding domain show functional heterogeneity: some mutants (R243W) lose transactivation and gain dominant-negative activity, while others (G173D, G173V, T193_Y194insR) show variable effects dependent on the specific response element tested (including PERP and COL18A1 REs relevant to clinical manifestations); structural modeling supported distinct functional effects. |
Yeast-based functional assay, mammalian cell transactivation assay, structural modeling of DBD mutations |
Human mutation |
Medium |
23463580
|
| 2014 |
ChIP-seq analysis revealed that TP53 and TP63 bind overlapping but distinct genomic cistromes using distinctive consensus motifs; in genotoxic stress, TP53 modulates TP63 binding events, resulting in global repression of cell-cycle/DNA-repair genes and activation of anti-proliferative/pro-apoptotic targets. In the absence of genotoxic stress, TP63 maintains expression of DNA repair genes. |
ChIP-seq integrated with microarray transcriptional analysis, cisplatin and adriamycin treatment |
Nucleic acids research |
High |
24823795
|
| 2016 |
ΔNp63α associates with TCF4 and co-occupies Wnt response elements (WREs) of MMP7 on chromatin, attenuating β-catenin recruitment; this represses WRE-driven transcription including MMP7 in SCC cells. ΔNp63α also appeared to interact with protein phosphatase PP2A, though GSK-3β phosphorylation and β-catenin nuclear localization were not altered by p63 loss. |
ChIP, co-immunoprecipitation, siRNA knockdown, luciferase reporter assay |
Cell cycle |
Medium |
26890356
|
| 2018 |
TP63 binds to the super-enhancer at the LINC01503 locus and activates its transcription in squamous cell carcinomas, as demonstrated by ChIP-seq and luciferase reporter assays. |
ChIP-seq, luciferase reporter assay |
Gastroenterology |
Medium |
29454790
|
| 2018 |
TP63 and SOX2 cooperatively activate lncRNA CCAT1 expression via its super-enhancers and promoter in SCCs; CCAT1 forms a complex with TP63 and SOX2 (shown by ChIRP analysis) that binds EGFR super-enhancers to activate MEK/ERK1/2 and PI3K/AKT signaling, driving SCC tumorigenesis. |
ChIRP analysis (chromatin isolation by RNA purification), ChIP-seq, siRNA knockdown, in vitro and in vivo tumor growth assays |
Nature communications |
High |
30190462
|
| 2018 |
TP63 (ΔNp63) expression is sufficient to install and sustain squamous-lineage enhancer landscapes and transcriptional signatures in human pancreatic ductal adenocarcinoma cells, promoting aggressive tumor phenotypes including enhanced motility, invasion, and accelerated tumor growth and metastasis in vivo. |
Ectopic ΔNp63 expression, enhancer landscape profiling (ChIP-seq), in vivo tumor models |
Cell reports |
High |
30428345
|
| 2019 |
IL-1β upregulates ΔNP63α specifically through the IL-1β/IL-1RI/β-catenin signaling pathway; elevated ΔNP63α then increases EGFR and Wip1 expression and decreases ATM, contributing to cisplatin resistance; silencing TP63 or inhibiting PI3K/AKT reversed the resistance. |
Loss-of-function siRNA assays, PI3K/AKT inhibition, Western blot, flow cytometry |
International journal of molecular sciences |
Medium |
30641908
|
| 2019 |
TP63 binds to transcriptional regulatory regions of ATDC (TRIM29) and KRT14, directly increasing their expression; ATDC and KRT14 execute a TP63-driven invasive program; in vivo, ATDC is required for TP63-induced bladder tumor invasion and metastasis. |
ChIP, reporter assay, shRNA knockdown, in vivo orthotopic tumor model |
Oncogene |
High |
30643195
|
| 2019 |
Wnt/β-catenin signaling in basal cells activates ΔN-TP63, which is necessary and sufficient to mediate Wnt-induced inhibition of epithelial cell specification; this mechanism is conserved across Xenopus, mouse, and human airway basal cells. |
Loss-of-function and gain-of-function experiments in Xenopus embryos, mouse airway, and human airway basal cell cultures; in vivo Wnt activation |
Cell reports |
High |
31553905
|
| 2019 |
TP63 directly regulates NRG1 expression in SCC cell lines; squamous tumors are dependent on NRG1 signaling in vivo, and NRG1 inhibition induces keratinization/terminal differentiation, blocking proliferation, identifying NRG1 as a critical TP63 downstream effector. |
ChIP demonstrating direct TP63 binding to NRG1 locus, genetically engineered mouse models, human xenograft models, NRG1 inhibition |
eLife |
High |
31144617
|
| 2019 |
Loss of TP63 in head and neck squamous epithelia accelerates tumor initiation and promotes HNSCC metastasis; TP63 loss-driven metastasis is mechanistically dependent on MAPK activation, as pharmacologic inhibition of MAPK by trametinib impaired metastasis in TP63 knockdown xenografts. |
Genetically engineered Trp63 conditional knockout mouse model, orthotopic xenograft assay, MAPK pharmacological inhibition |
Molecular cancer research |
High |
30910837
|
| 2020 |
TP63 (ΔNp63α) acts as a pioneer transcription factor that binds closed chromatin, enhances chromatin accessibility at epidermal enhancers, coordinates chromatin-remodeling enzymes to orchestrate tissue-specific enhancer landscapes and 3D chromatin architecture; in SCCs it establishes squamous-like enhancer landscapes to drive oncogenic target expression. |
ATAC-seq, ChIP-seq, Hi-C/chromosome conformation capture, chromatin remodeling enzyme co-immunoprecipitation (reviewed/synthesized from multiple studies) |
Cellular and molecular life sciences |
Medium |
32447427
|
| 2020 |
TP63, SOX2, and KLF5 form a core regulatory circuitry in ESCC cells that determines chromatin accessibility and gene expression; direct interactions between the TP63 promoter and distal functional enhancers were verified by circular chromosome conformation capture; knockdown of any one factor reduces viability; super-enhancer regulation of ALDH3A1 mediated by this circuitry is required for ESCC viability. |
ChIP-seq, ATAC-seq, circular chromosome conformation capture sequencing (4C-seq), CRISPR/Cas9 enhancer deletion, shRNA knockdown, xenograft tumor assays |
Gastroenterology |
High |
32619460
|
| 2020 |
Tp63 deletion by CRISPR/Cas9 in ES cells halted basal (TP63+/KRT5+) and airway epithelial cell differentiation on decellularized lung scaffolds, demonstrating that TP63 is indispensable for endoderm-to-proximal airway differentiation via basal cell intermediates. |
CRISPR/Cas9 gene deletion in ES cells, decellularized lung scaffold recellularization assay, immunostaining |
NPJ Regenerative medicine |
Medium |
33674599
|
| 2020 |
Tp63-expressing epithelial stem cells from non-skin organs (cornea, oesophagus, vagina, bladder, prostate) can respond to skin morphogenetic signals and contribute to hair follicles and epidermis renewal in vivo, demonstrating that Tp63 expression confers latent skin (epidermal lineage) competence to diverse epithelial stem cells. |
Transplantation of non-skin Tp63+ epithelial stem cells into newborn skin microenvironment, lineage tracing, immunostaining |
Nature communications |
Medium |
33159086
|
| 2021 |
DLX5 cooperates with TP63 to co-regulate approximately 2000 enhancers and promoters converging on cancer-promoting pathways in SCCs; DLX5 promoter activation in ESCC is directly mediated by SOX2 (distinct from TP63-driven regulation). |
ChIP-seq, epigenomic profiling, siRNA knockdown, in vitro and in vivo viability assays |
Nucleic acids research |
Medium |
34370013
|
| 2022 |
TP63 missense variants that disrupt the C-terminal transactivation-inhibitory domain (TID) cause constitutive p63 tetramer formation and constitutive transcriptional activation (demonstrated by blue-native PAGE and luciferase reporter assays), leading to premature ovarian insufficiency by promoting oocyte apoptosis. |
Blue-native PAGE, luciferase reporter assay, functional characterization of patient-derived variants |
Human mutation |
Medium |
35801529
|
| 2023 |
TP63 gain-of-function mutations impairing the TID cause constitutive TAp63α tetramer formation and activation, inducing oocyte apoptosis through increased expression of apoptosis-inducing factors; knock-in mice with p63+/ΔTID or p63+/R647C showed rapid oocyte depletion via apoptosis, confirming the mechanism of POI. |
In vitro functional assay of mutant protein activity, CRISPR knock-in mouse models (p63+/ΔTID and p63+/R647C), oocyte counting, apoptosis assays |
The Journal of clinical investigation |
High |
36856110
|
| 2023 |
TP63 fusions (e.g., TBL1XR1::TP63) act as oncogenes; they coordinate recruitment of two epigenetic complexes — NCoR-HDAC3 (via the N-terminal fusion partner) and KMT2D (via the C-terminal TP63 component) — at enhancers, driving a cell state with upregulation of MYC, EED, and EZH2. EZH2 inhibition with valemetostat is highly effective in TP63 fusion-positive lymphoma models and in a patient. |
Transgenic mouse models, ChIP-seq, co-immunoprecipitation of epigenetic complexes, xenograft models, patient-derived xenografts, clinical case |
Science translational medicine |
High |
37729434
|
| 2023 |
YAP/TAZ, TEAD, and TP63 form a converged transcriptional complex in bronchial epithelial cells that cooperatively promotes basal cell proliferation and represses immune/interferon responses (including repression of MHC Class II transactivator CIITA), as defined by combined ChIP-seq and siRNA depletion RNA-seq experiments. |
ChIP-seq, siRNA depletion followed by RNA-seq, integration with human premalignant lesion gene expression data |
Journal of experimental & clinical cancer research |
Medium |
37150829
|
| 2024 |
TP63 and STAT1 mutually suppress each other at the transcriptional level by co-occupying and co-regulating each other's promoters and enhancers; TP63 inhibition leads to increased IFNγ signaling, enhanced CD8+ T cell infiltration, and increased tumor killing in syngeneic mouse models and ex vivo co-culture systems, and TP63 silencing enhances efficacy of PD-1 blockade. |
ChIP-seq (co-occupancy), syngeneic mouse tumor models, ex vivo co-culture T cell killing assay, siRNA knockdown, combinatorial immunotherapy experiments |
Nature communications |
High |
38509096
|
| 2024 |
TDP-43 post-transcriptionally stabilizes TP63 mRNAs (as an RNA-binding protein) and also transcriptionally activates TP63 by binding its promoter; reciprocally, TP63 binds the TDP-43 promoter to activate TDP-43 transcription, forming a positive feedback circuit in ESCC cells. |
RNA-binding assays, ChIP/promoter binding assays, RNA stability assays, knockdown/overexpression experiments |
Advanced science |
Medium |
39023169
|
| 2019 |
BCR stimulation induces p63 protein expression in aggressive CLL subset #8 and promotes CLL cell survival; siRNA-mediated downregulation of p63 increased apoptosis in subset #8 cells, establishing p63 as a pro-survival factor in this CLL subset. |
BCR stimulation assay, siRNA knockdown, apoptosis assay |
International journal of cancer |
Medium |
30447004
|
| 2010 |
A missense variant (V405M) in the TP63 oligomerization domain found in patients with orofacial clefting abrogates oligomerization of mutant p63 protein into oligomeric complexes, indicating loss-of-function rather than dominant-negative mechanism, and supporting dosage-dependent functions of p63. |
Biochemical oligomerization assay of patient-derived variant protein |
European journal of human genetics |
Medium |
30850703
|
| 2010 |
Ozone treatment promotes Tp63-mediated transcription of KRT10 in basal keratinocytes; Tp63 was shown by ChIP to directly bind the KRT10 promoter; silencing Tp63 reversed ozone-induced KRT10 upregulation and keratinocyte differentiation. |
ChIP, siRNA knockdown, RT-PCR, Western blot, in vivo psoriasis mouse model |
Journal of cellular and molecular medicine |
Medium |
32168425
|