Affinage

TP63

Tumor protein 63 · UniProt Q9H3D4

Round 2 corrected
Length
680 aa
Mass
76.8 kDa
Annotated
2026-04-28
130 papers in source corpus 36 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TP63 is a master transcriptional regulator of epithelial development, stem cell maintenance, and stress-responsive apoptosis, operating through multiple isoforms—ΔNp63 variants that sustain basal/stem cell identity and TAp63 variants that mediate DNA-damage-induced oocyte elimination, metastasis suppression, and metabolic reprogramming. ΔNp63α acts as a pioneer factor that opens epidermal enhancers in non-accessible chromatin, cooperates with SOX2 and KMT2D at super-enhancers, transcriptionally activates adhesion and survival programs (including integrin α6β4 and DKK3), and antagonizes p53, p73, and Notch1-driven differentiation (PMID:31296872, PMID:30190462, PMID:29440247, PMID:16715076, PMID:16618808). TAp63 directly transactivates Dicer, miR-130b, GLS2, and DNA repair genes (BRCA2, Rad51) to suppress metastasis and maintain genomic integrity, and in oocytes undergoes CHK1/CHK2-dependent phosphorylation to trigger apoptotic elimination of damaged germ cells (PMID:20962848, PMID:23574722, PMID:19816568, PMID:17122775). Heterozygous missense mutations in the p63 DNA-binding domain cause EEC syndrome through loss of DNA binding and dominant-negative inhibition of wild-type p63 (PMID:10535733).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Cloning of the p63 gene resolved how a p53 family member could generate both transactivating and dominant-negative isoforms from a single locus, establishing the TA/ΔN isoform framework that underlies all subsequent functional studies.

    Evidence Degenerate PCR cloning with transfection/reporter and apoptosis assays in p53-deficient cells

    PMID:9662378 PMID:9774969

    Open questions at the time
    • Relative contributions of individual isoforms in vivo were not resolved
    • Structural basis of dominant-negative inhibition unknown at this stage
  2. 1999 High

    Identification of p63 DNA-binding domain mutations as the cause of EEC syndrome established TP63 as a disease gene and demonstrated that dominant-negative and loss-of-function mechanisms explain autosomal dominant limb-ectodermal malformations.

    Evidence Positional cloning across multiple families, transactivation reporter assays with mutant p63

    PMID:10535733

    Open questions at the time
    • Enhancer-level consequences of EEC mutations not yet explored
    • Genotype-phenotype correlation across different syndromes (AEC, SHFM) not addressed
  3. 2001 High

    The discovery that p63 marks epithelial stem cells (holoclones) and is required for prostate and Müllerian duct organogenesis defined TP63 as a master regulator of epithelial stem cell identity rather than merely a p53-like tumor suppressor.

    Evidence Clonal analysis with immunofluorescence in keratinocytes/limbal cells; p63-null mouse analysis of prostate and Müllerian duct development; tissue recombination experiments

    PMID:11106548 PMID:11248048 PMID:11795399

    Open questions at the time
    • Downstream target genes mediating stem cell maintenance not yet identified
    • Mechanism of ΔNp63α-specific stem cell function versus other isoforms unclear
  4. 2001 High

    Demonstration that tumor-derived mutant p53 proteins directly bind and inhibit p63 through core-domain interaction revealed a gain-of-function oncogenic mechanism exploiting p63 inactivation.

    Evidence Co-immunoprecipitation in tumor cells, in vitro binding with purified proteins, reporter assays

    PMID:11238924

    Open questions at the time
    • Structural details of mutant-p53/p63 interface unknown
    • Relative importance of p63 versus p73 inhibition for tumor phenotype not dissected
  5. 2002 High

    Genetic epistasis experiments established that p63 and p73 are required for p53-dependent apoptosis after DNA damage, repositioning p63 as a functional node downstream of p53 in the damage response rather than a redundant paralog.

    Evidence Double-knockout MEFs with E1A sensitization, in vivo DNA damage models

    PMID:11932750

    Open questions at the time
    • Whether p63 contribution is direct transcriptional or via p53 stabilization not fully resolved
    • Isoform-specific requirements in the apoptotic response not determined
  6. 2006 High

    A burst of mechanistic studies identified key regulatory inputs and outputs: TAp63 monitors oocyte DNA integrity via phosphorylation-dependent activation; ΔNp63α maintains epithelial survival through cell adhesion gene regulation and β4-integrin signaling; Itch/AIP4 controls p63 turnover via ubiquitination at specific lysines; Notch1 and p63 operate in a reciprocal antagonistic loop controlling keratinocyte differentiation; and ΔNp63α promotes survival in SCC by suppressing p73-dependent apoptosis.

    Evidence TAp63-null mouse oocyte analysis; RNAi/overexpression adhesion and anoikis assays; co-IP and ubiquitination assays identifying Itch/critical lysines; ChIP and reporter assays for Notch1-Hes1 regulation; ChIP and co-IP for p63-p73 axis in HNSCC

    PMID:16413471 PMID:16618808 PMID:16715076 PMID:16861923 PMID:17122775

    Open questions at the time
    • Kinase(s) responsible for TAp63 phosphorylation in oocytes not fully identified at this stage
    • Structural basis of Itch-p63 recognition not resolved
    • Whether Notch-p63 antagonism operates in all stratified epithelia or is tissue-restricted
  7. 2008 High

    Identification of miR-203 as a direct post-transcriptional repressor of ΔNp63 revealed a non-coding RNA switch that terminates stem cell self-renewal during epithelial differentiation.

    Evidence 3′-UTR reporter assays, miR-203 overexpression reducing clonogenic capacity in primary keratinocytes

    PMID:18483491

    Open questions at the time
    • Upstream signals inducing miR-203 during differentiation not fully characterized
    • Whether miR-203 is the sole physiological miRNA regulator of p63 in vivo unknown
  8. 2009 High

    Discovery of a TGFβ/Smad/mutant-p53 ternary complex that antagonizes p63 function explained how TGFβ signaling switches from tumor suppression to metastasis promotion in cancers harboring p53 mutations.

    Evidence Co-IP of ternary complex, RNAi, invasion/migration assays, mouse metastasis models

    PMID:19345189

    Open questions at the time
    • Stoichiometry and structural details of the ternary complex not resolved
    • Which specific p63 target genes are most relevant for metastasis suppression not fully defined
  9. 2010 High

    TAp63 was shown to directly transactivate Dicer and regulate miR-130b to suppress metastasis, and separately to activate GLS2 for antioxidant defense, establishing TAp63 as a coordinator of both miRNA biogenesis and metabolic reprogramming.

    Evidence ChIP and reporter assays at Dicer and GLS2 promoters, in vivo metastasis models, oxidative stress assays

    PMID:20962848 PMID:23574722

    Open questions at the time
    • Full spectrum of TAp63 metabolic targets not mapped
    • Whether Dicer regulation by TAp63 is relevant outside metastasis context not tested
  10. 2015 High

    Genome-wide ChIP-seq revealed that p63 bookmarks enhancers across differentiation states and that enhancer activity (H3K27ac), not p63 binding per se, determines transcriptional output — explaining how the same factor governs distinct gene programs in epidermis versus limb.

    Evidence ChIP-seq for p63 and H3K27ac in differentiating primary human keratinocytes, cross-tissue comparison

    PMID:26034101

    Open questions at the time
    • Cofactors determining which bookmarked enhancers become active not identified
    • 3D chromatin architecture at bookmarked loci not characterized
  11. 2018 High

    Multiple studies converged to define the chromatin-level mechanism: KMT2D physically interacts with p63 and deposits H3K4me1 at p63-bound enhancers; SOX2 and p63 co-occupy super-enhancers in SCC to regulate EGFR via lncRNA CCAT1; BRD4 and FOXO1 maintain TP63 expression itself through enhancer regulation; and EEC mutations rewire the enhancer landscape with ectopic RUNX1 activation.

    Evidence Co-IP and ChIP-seq for KMT2D-p63; ChIRP for CCAT1-p63-SOX2 complex; BRD4 ChIP-seq with BET inhibition and FOXO manipulation; ATAC-seq and H3K27ac ChIP-seq in EEC patient keratinocytes with RUNX1 rescue

    PMID:27980063 PMID:29440247 PMID:30190462 PMID:30566872

    Open questions at the time
    • Whether KMT2D-p63 interaction is direct or bridged by additional factors not resolved
    • Full enhancer rewiring atlas across different p63 mutation classes not available
    • Relative contributions of CCAT1-dependent versus CCAT1-independent p63-SOX2 programs unknown
  12. 2019 High

    In vivo demonstration that p63 functions as a bona fide pioneer factor—binding closed chromatin at epidermal enhancers to initiate opening—resolved a longstanding question about whether p63 bookmarking reflects passive binding or active chromatin remodeling.

    Evidence tp63 knockout zebrafish with ATAC-seq showing loss of accessibility at epidermal enhancers, ChIP-seq for binding dynamics

    PMID:31296872

    Open questions at the time
    • Chromatin remodelers recruited by p63 to open chromatin not identified
    • Whether pioneer activity is conserved in mammalian embryonic epidermis not directly shown
  13. 2020 High

    Genetic epistasis in zebrafish clarified that p63 mediates ER-stress and oxidative-stress apoptosis via Puma (distinct from p53-dependent genotoxic apoptosis), and CHK1 signals to both TAp63 and p53 semi-redundantly for oocyte quality control.

    Evidence CRISPR null alleles of puma, p53, p63, p73 in zebrafish; stress-specific apoptosis assays; CHK1/CHK2 epistasis

    PMID:32273296 PMID:34193827

    Open questions at the time
    • Mechanistic basis for stress-type specificity of p63 versus p53 not determined
    • Whether CHK1-TAp63 axis operates in mammalian oocytes under physiological damage levels not confirmed
  14. 2022 High

    Structural studies established that TAp63α forms a unique autoinhibited dimer (unlike constitutively tetrameric p53 and p73), explaining why TAp63 activation requires signal-dependent conformational switching, and confirmed that MDM2 does not ubiquitinate p63 despite binding it.

    Evidence Structural analysis and domain architecture comparison with biochemical validation

    PMID:35314772

    Open questions at the time
    • High-resolution structure of the full-length autoinhibited dimer not available
    • Mechanism by which phosphorylation triggers dimer-to-tetramer transition not structurally resolved
  15. 2024 High

    Lineage tracing demonstrated that p63-expressing progenitors essential for alveolar regeneration originate from airway secretory cells, extending p63's stem cell function beyond classical stratified epithelia to injury-induced lung repair.

    Evidence Dual recombinase lineage tracing, single-cell RNA-seq, p63 loss-of-function in vivo mouse lung injury

    PMID:39232560

    Open questions at the time
    • Signals activating p63 in secretory cells upon injury not defined
    • Whether these progenitors contribute to pathological remodeling (fibrosis) not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of the TAp63α dimer-to-tetramer transition upon phosphorylation, the identity of chromatin remodelers recruited by p63 during pioneer-factor activity, and the full target gene network distinguishing ΔNp63 stem cell maintenance from TAp63 tumor suppression across tissue types.
  • Full-length TAp63α dimer structure at atomic resolution not available
  • Chromatin remodeling machinery directly recruited by pioneer p63 not identified
  • Comprehensive isoform-resolved cistrome across multiple epithelial tissues lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 10 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 6
Pathway
R-HSA-74160 Gene expression (Transcription) 10 R-HSA-1266738 Developmental Biology 4 R-HSA-5357801 Programmed Cell Death 4 R-HSA-162582 Signal Transduction 3 R-HSA-4839726 Chromatin organization 3 R-HSA-73894 DNA Repair 1
Partners
BRD4ITCHKMT2DMDM2RUNX1SOX2TP53TP73
Complex memberships
SOX2-p63 super-enhancer complexmutant-p53/Smad/p63 ternary complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 p63 (p51/p63) was cloned and shown to encode multiple isoforms with transactivating, dominant-negative, and apoptosis-inducing activities; the predominant isoforms in many epithelial tissues lack an N-terminal transactivation domain and act as dominant-negative inhibitors of p53 and TA-p63 transactivation of p53 reporter genes. Degenerate PCR cloning, transfection/reporter assays, apoptosis assays in p53-deficient cells Molecular cell High 9662378 9774969
1999 Heterozygous missense mutations in the p63 DNA-binding domain cause EEC syndrome; eight mutations predicted to abolish DNA binding capacity of p63, with transactivation studies confirming loss of function and dominant-negative mechanism explaining autosomal dominant inheritance. Positional cloning, mutation analysis, transactivation reporter assays with mutant p63 isoforms Cell High 10535733
2000 p63 is expressed in prostate basal cells (predominantly DeltaNp63alpha isoform) and is required for prostate development; p63−/− mice fail to develop the prostate, demonstrating an essential role for p63 in prostate organogenesis. Immunohistochemistry, RT-PCR, p63 knockout mouse analysis The American journal of pathology High 11106548
2001 p63 distinguishes keratinocyte stem cells (holoclones) from transient amplifying (TA) cells (paraclones); p63 is abundantly expressed by epidermal and limbal holoclones but undetectable in paraclones, and 14-3-3σ promotes clonal evolution from stem to TA cells with concomitant p63 reduction. Clonal analysis, immunofluorescence, 14-3-3σ siRNA knockdown, serial cultivation PNAS High 11248048
2001 Tumor-derived mutant p53 proteins interact directly with p63 (and p73) through the p53 core domain, downregulating p63 and p73 transcriptional activity; wild-type p63 and p73 also interact with each other when co-expressed. Co-immunoprecipitation in tumor cell lines, in vitro binding with purified proteins, transfection reporter assays, PAb240 antibody epitope mapping Molecular and cellular biology High 11238924
2001 p63 determines Müllerian duct epithelial cell fate: vaginal mesenchyme induces p63 expression in uterine epithelium causing vaginal differentiation, and p63-null Müllerian vaginal epithelium develops as uterine epithelium instead of vaginal epithelium. Tissue recombination experiments, p63-null mouse analysis, immunohistochemistry Annals of the New York Academy of Sciences High 11795399
2002 p63 and p73 are required for p53-dependent apoptosis in response to DNA damage; combined loss of p63 and p73 in mouse embryo fibroblasts prevents p53-mediated apoptosis after DNA damage, establishing genetic epistasis downstream of DNA damage signaling. Mouse embryo fibroblasts with genetic deletions of p53 family members, E1A oncogene-sensitized apoptosis assay, in vivo DNA damage model Nature High 11932750
2002 TAp63alpha (p51B) protein is stabilized in response to genotoxic stress (UV-C, DNA-damaging drugs) by a post-transcriptional mechanism involving Ser/Thr phosphorylation and proteasomal regulation; unlike p53, TAp63alpha does not form an immunoprecipitable complex with MDM2. Western blot, anti-MDM2 immunoprecipitation, proteasome inhibitor MG132, okadaic acid (Ser/Thr phosphatase inhibitor) treatment Experimental cell research Medium 12027449
2000 p63 gene amplification (named AIS locus) occurs in squamous cell carcinoma of lung and head and neck, accompanied by overexpression of the DeltaN isoform; overexpression of p40/AIS in Rat 1a cells increased soft agar growth and tumor size in mice, demonstrating oncogenic activity. FISH, RT-PCR, Western blot, soft agar colony assay, mouse xenograft PNAS High 10805802
2006 TAp63 is constitutively expressed in female germ cells during meiotic arrest and is essential for DNA damage-induced oocyte death; DNA damage induces phosphorylation of TAp63 and its binding to p53 cognate DNA sites, leading to oocyte elimination. Immunohistochemistry, TAp63-null mouse analysis, DNA damage assays, phosphorylation studies, DNA binding assays Nature High 17122775
2006 p63 knockdown in mammary epithelial cells and keratinocytes causes downregulation of cell adhesion-associated genes, cell detachment, and anoikis; overexpression of TAp63gamma or DeltaNp63alpha upregulates cell adhesion molecules and confers resistance to anoikis; apoptosis induced by p63 loss is rescued by signaling downstream of beta4 integrin. RNAi knockdown, overexpression, transcriptional profiling, adhesion assays, anoikis assays, beta4 integrin epistasis Nature cell biology High 16715076
2006 DeltaNp63alpha promotes survival in squamous cell carcinoma by suppressing p73-dependent apoptosis; p63 knockdown induces proapoptotic Puma and Noxa via p73, and DeltaNp63alpha inhibits p73 transcriptional activity through both direct promoter binding and physical interaction with p73. RNAi, co-immunoprecipitation, chromatin immunoprecipitation, apoptosis assays in HNSCC cells Cancer cell High 16413471
2006 Notch1 activation suppresses p63 expression in keratinocytes through a mechanism requiring down-modulation of IRF7 and/or IRF3, independent of cell cycle withdrawal; conversely, elevated p63 counteracts Notch1-dependent growth restriction and differentiation, and p63 directly represses the Notch1 target Hes-1. Retroviral overexpression, RNAi, reporter assays, ChIP, genetic mouse models Genes & development High 16618808
2006 Itch/AIP4, a HECT E3 ubiquitin ligase, physically associates with p63 and promotes its degradation; two critical lysine residues in a specific region of p63 (associated with SHFM-4 syndrome) are required for Itch-mediated p63 ubiquitination and degradation. Co-immunoprecipitation, p63 deletion mutant analysis, ubiquitination assays, proteasome inhibitor experiments Cell cycle High 16861923
2007 DeltaNp63alpha (DeltaNp51B) maintains keratinocyte stem cell immaturity by inhibiting Notch1-dependent growth arrest and differentiation, and induces expression of integrin alpha6beta4, which promotes attachment of basal cells to basement membrane. Retroviral overexpression of DeltaNp63alpha in mouse keratinocytes, Notch1 activation assays, integrin expression analysis Oncogene Medium 17237812
2009 TGFbeta, in concert with oncogenic Ras and mutant p53, induces assembly of a mutant-p53/p63 ternary complex in which Smads serve as essential platforms, antagonizing p63 functions and enabling TGFbeta-dependent cell migration, invasion, and metastasis. Co-immunoprecipitation of ternary complex, RNAi, invasion/migration assays, mouse metastasis models, clinical tumor cohort Cell High 19345189
2009 p63 (TAp63) and p73 transcriptionally regulate DNA repair genes including BRCA2, Rad51, and mre11; cells deficient in p63 and p73 show impaired DNA repair, and p63+/−;p73+/− mice develop mammary tumors. Genome-wide expression analysis, ChIP, luciferase reporter assays, DNA repair functional assays, mouse tumor models PLoS genetics High 19816568
2010 TAp63 suppresses metastasis by coordinately transactivating Dicer and regulating miR-130b; TAp63 directly binds the Dicer promoter to activate transcription, and modulation of Dicer and miR-130b markedly affects metastatic potential of TAp63-deficient cells. ChIP, luciferase reporter assays, RNAi, overexpression, in vivo mouse metastasis models, miRNA profiling Nature High 20962848
2013 TAp63 directly binds the p53/p63 consensus DNA binding sequence within the GLS2 (glutaminase 2) promoter to activate transcription; TAp63-dependent GLS2 expression promotes cellular antioxidant defense, and GLS2 depletion sensitizes cells to ROS-induced apoptosis. ChIP, luciferase reporter assay, siRNA knockdown, oxidative stress assays Cell cycle High 23574722
2014 Mutant p53 proteins with conformational changes (e.g., R175H) bind p63 and p73 strongly, while contact mutants (e.g., R273H) bind more weakly; MDM2 competes with p63 for binding to p53R175H (relieving p63 inhibition) but forms a trimeric complex with p73 and p53R273H to enhance p73 inhibition. Co-immunoprecipitation, MDM2 binding/competition assays, transcriptional reporter assays, invasion assays Oncogene High 25417702
2015 p63 bookmarks genomic loci at single and clustered enhancers; the activity of p63-bound enhancers (marked by H3K27ac) determines gene expression dynamics during keratinocyte differentiation rather than p63 binding per se, and inactive p63-bound enhancers in keratinocytes correspond to active enhancers in limb development. ChIP-seq for p63 and H3K27ac, epigenome profiling of differentiating primary human keratinocytes, comparison across tissues EMBO reports High 26034101
2018 KMT2D (MLL4) physically interacts with p63 genome-wide and is enriched at p63 target enhancers; depletion of KMT2D reduces H3K4me1 and H3K27ac at p63-bound enhancers and decreases expression of p63 target genes, linking KMT2D to p63-dependent epithelial gene regulation. Co-IP, ChIP-seq, RNA-seq, siRNA knockdown in epidermal keratinocytes Genes & development High 29440247
2018 TP63 and SOX2 cooperatively activate lncRNA CCAT1 via super-enhancers; CCAT1 forms a complex with TP63 and SOX2 (demonstrated by ChIRP), and this complex regulates EGFR expression at EGFR super-enhancers, activating MEK/ERK1/2 and PI3K/AKT signaling in squamous cell carcinomas. ChIP-seq, CCAT1 ChIRP analysis, siRNA knockdown, luciferase assays, in vitro and in vivo tumor growth assays Nature communications High 30190462
2018 p63 mutations in the DNA-binding domain (EEC syndrome) rewire the enhancer landscape in patient-derived keratinocytes: p63 mutant cells lose p63-bound active enhancers and gain new enhancers bound by deregulated RUNX1; reversing RUNX1 overexpression partially rescues the altered gene expression and enhancer landscape. ATAC-seq, H3K27ac ChIP-seq, RNA-seq, RUNX1 knockdown in EEC patient-derived keratinocytes Cell reports High 30566872
2019 In zebrafish embryos, p63 acts as a pioneer transcription factor by binding non-accessible chromatin at epidermal enhancers, promoting chromatin opening and epidermal gene expression; during early development, p63 also limits Sox3 binding at neural enhancers, reducing neural gene expression. tp63 knockout zebrafish, ATAC-seq, ChIP-seq for p63 binding dynamics, co-expression analysis of p63/Sox3 in neural plate border Nature communications High 31296872
2020 In zebrafish, p63 is specifically required for ER stress-induced and oxidative stress-induced apoptosis (mediated via Puma), but not for genotoxic stress-induced apoptosis (which requires p53); CHK1 becomes activated by persistent DSBs in oocytes and signals to both TRP53 and TAp63 in a semi-redundant pathway for oocyte elimination. Zebrafish null alleles of puma, noxa, p53, p63, p73 by CRISPR/knock-in, in vivo stress assays, CHK1/CHK2 epistasis Cell death & disease / Genetics High 32273296 34193827
2022 TAp63α forms an autoinhibited dimeric state (unique among p53 family members, which are constitutively tetrameric); the oligomerization domain of p63 contains an additional helix required for stabilizing tetrameric states; MDM2 binds all three p53 family members but ubiquitinates only p53; the non-divided transactivation domain of p63 has constitutively high activity unlike the bipartite regulated TADs of p53/p73. Structural analysis, domain architecture comparison, protein biochemistry Cell death and differentiation High 35314772
2006 TA-p63gamma stabilizes and activates the DeltaN-p63 promoter; in cells lacking p53, TA-p63gamma accumulates and drives DeltaN-p63 expression; when p53 is present, it destabilizes TA-p63gamma via proteasome-dependent degradation, reducing DeltaN-p63 expression. Promoter reporter assays, proteasome inhibition, ectopic p53 expression, siRNA knockdown Oncogene Medium 16331262
2018 BRD4 is required for maintaining p63 (TP63) expression in basal mammary epithelial cells through FOXO transcription factor-dependent enhancer regulation; FOXO1 activation (via EGFR-AKT inhibition) promotes TP63 expression, while Src kinase activation and FOXO1 inhibition decrease TP63 expression. BRD4 ChIP-seq, BET inhibitor treatment, FOXO1 activation/inhibition, RNA-seq in non-transformed mammary cells Nucleic acids research Medium 27980063
2018 p63 binds to the upstream regulatory region of the DKK3 gene to drive its expression in esophageal squamous cell carcinoma; p63 knockdown decreases DKK3 expression, and DKK3 signals through CKAP4 as a receptor to promote cancer cell proliferation. ChIP demonstrating p63 binding to DKK3 upstream region, siRNA knockdown, DKK3 re-expression rescue, organoid assays Cancer research Medium 30181180
2005 In corneal limbal stem cells, the DeltaNp63alpha isoform (not beta or gamma) is specifically expressed in holoclones (stem cells); upon corneal wounding, alpha-isoform-expressing cells migrate from the limbus through the corneal epithelium; beta and gamma isoforms appear suprabasally during corneal regeneration, suggesting isoform-specific roles in stem cell maintenance versus differentiation. Isoform-specific RT-PCR, immunofluorescence, clonal analysis (holoclones/meroclones/paraclones), limbal ablation experiments PNAS High 15983386
2008 miR-203 specifically targets the 3'-UTR of p63 (DeltaNp63) mRNA; miR-203 overexpression in proliferating keratinocytes reduces clonogenic capacity and is induced during keratinocyte differentiation, establishing a miR-203/DeltaNp63 regulatory axis controlling epithelial stemness. 3'-UTR reporter assays, miRNA overexpression in primary keratinocytes, clonogenic assays, embryonic stem cell differentiation Cell death and differentiation High 18483491
2024 p63-expressing progenitors that emerge upon lung injury originate from airway secretory cells and differentiate into alveolar type 1 and type 2 cells; p63 activation is functionally essential for efficient alveolar regeneration from secretory cells post-injury. Dual recombinase sequential genetic lineage tracing, single-cell RNA-seq, clonal analysis, p63 loss-of-function in vivo Cell stem cell High 39232560
2014 In squamous cell carcinomas, SOX2 preferentially interacts with p63 (rather than OCT4 as in ES cells); SOX2 and p63 exhibit overlapping genomic occupancy at a large number of SCC-specific loci and jointly regulate gene expression including the oncogene ETV4, which is essential for SOX2-amplified SCC cell survival. ChIP-seq, co-IP for SOX2-p63 interaction, siRNA knockdown, cell viability assays Journal of Clinical Investigation High 24590290

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Molecular cell 1849 9774969
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2001 p63 identifies keratinocyte stem cells. Proceedings of the National Academy of Sciences of the United States of America 1142 11248048
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2002 p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature 699 11932750
2009 A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell 683 19345189
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2010 An atlas of combinatorial transcriptional regulation in mouse and man. Cell 573 20211142
1999 Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome. Cell 566 10535733
1998 Cloning and functional analysis of human p51, which structurally and functionally resembles p53. Nature medicine 476 9662378
2006 p63 protects the female germ line during meiotic arrest. Nature 457 17122775
2000 p63 is a prostate basal cell marker and is required for prostate development. The American journal of pathology 453 11106548
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2002 p63 expression profiles in human normal and tumor tissues. Clinical cancer research : an official journal of the American Association for Cancer Research 437 11839669
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2002 On the shoulders of giants: p63, p73 and the rise of p53. Trends in genetics : TIG 429 11818141
2014 p63(+)Krt5(+) distal airway stem cells are essential for lung regeneration. Nature 428 25383540
2016 Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. Cell 423 26871637
2000 AIS is an oncogene amplified in squamous cell carcinoma. Proceedings of the National Academy of Sciences of the United States of America 422 10805802
2000 P63 and P73: P53 mimics, menaces and more. Nature reviews. Molecular cell biology 419 11252895
1996 Normalization and subtraction: two approaches to facilitate gene discovery. Genome research 401 8889548
2001 A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Molecular and cellular biology 395 11238924
2004 p63 and p73: roles in development and tumor formation. Molecular cancer research : MCR 392 15280445
2006 p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis. Cancer cell 378 16413471
2001 Physical interaction with Yes-associated protein enhances p73 transcriptional activity. The Journal of biological chemistry 374 11278685
2010 A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nature genetics 369 20972438
2014 Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nature genetics 368 24880342
2006 p63 regulates an adhesion programme and cell survival in epithelial cells. Nature cell biology 365 16715076
2010 TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 360 20962848
2008 miR-203 represses 'stemness' by repressing DeltaNp63. Cell death and differentiation 344 18483491
2008 Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nature genetics 341 18794855
2005 Isoforms of DeltaNp63 and the migration of ocular limbal cells in human corneal regeneration. Proceedings of the National Academy of Sciences of the United States of America 341 15983386
2006 Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes & development 338 16618808
2011 A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese. Nature genetics 325 21725308
2002 Differential expression of p63 isoforms in normal tissues and neoplastic cells. The Journal of pathology 255 12434410
2003 Functional regulation of p73 and p63: development and cancer. Trends in biochemical sciences 247 14659698
2007 p63-associated disorders. Cell cycle (Georgetown, Tex.) 242 17224651
2018 STAT3, stem cells, cancer stem cells and p63. Cellular & molecular biology letters 217 29588647
2011 p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53. Cell death and differentiation 204 21760596
2018 Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression. Nature communications 190 30190462
2010 p63 in epithelial survival, germ cell surveillance, and neoplasia. Annual review of pathology 189 20078223
2009 Crosstalk of Notch with p53 and p63 in cancer growth control. Nature reviews. Cancer 163 19609265
2004 p63: Molecular complexity in development and cancer. Carcinogenesis 154 15033906
2002 The p63 gene in EEC and other syndromes. Journal of medical genetics 152 12070241
2004 The role of p63 in development and differentiation of the epidermis. Journal of dermatological science 151 14757276
2014 SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas. The Journal of clinical investigation 147 24590290
2017 Master regulatory role of p63 in epidermal development and disease. Cellular and molecular life sciences : CMLS 136 29103147
2006 Pattern of p63 mutations and their phenotypes--update. American journal of medical genetics. Part A 135 16691622
2015 Transcription factor p63 bookmarks and regulates dynamic enhancers during epidermal differentiation. EMBO reports 133 26034101
2002 p63 expression in normal skin and usual cutaneous carcinomas. Journal of cutaneous pathology 133 12358808
2000 p63 and p73 transactivate differentiation gene promoters in human keratinocytes. Biochemical and biophysical research communications 124 10873608
2013 p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis. Nature reviews. Cancer 123 23344544
2015 Maintaining epithelial stemness with p63. Science signaling 122 26221054
1998 A second p53-related protein, p73L, with high homology to p73. Biochemical and biophysical research communications 121 9703973
2014 How the TP53 family proteins TP63 and TP73 contribute to tumorigenesis: regulators and effectors. Human mutation 115 24488880
2009 p63 and p73 transcriptionally regulate genes involved in DNA repair. PLoS genetics 115 19816568
1999 Structure, function and regulation of p63 and p73. Cell death and differentiation 108 10637429
2001 p53, p63 and p73--solos, alliances and feuds among family members. Biochimica et biophysica acta 104 11825686
2000 Evolution of functions within the p53/p63/p73 family. Annals of the New York Academy of Sciences 104 11193045
2014 Functional interplay between MDM2, p63/p73 and mutant p53. Oncogene 95 25417702
2007 The roles of p63 in cancer. Cell cycle (Georgetown, Tex.) 92 17264676
2002 P63 gene mutations and human developmental syndromes. American journal of medical genetics 91 12357472
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2007 Control of keratinocyte proliferation and differentiation by p63. Cell cycle (Georgetown, Tex.) 76 17264679
2019 Molecular Mechanisms of p63-Mediated Squamous Cancer Pathogenesis. International journal of molecular sciences 75 31340447
2020 p63-related signaling at a glance. Journal of cell science 74 32917730
2013 p63 regulates glutaminase 2 expression. Cell cycle (Georgetown, Tex.) 72 23574722
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2008 Giant cell tumor of bone express p63. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 59 18311114
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2001 Roles of p63 in differentiation of Müllerian duct epithelial cells. Annals of the New York Academy of Sciences 55 11795399
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2007 Conflicting roles for p63 in skin development and carcinogenesis. Cell cycle (Georgetown, Tex.) 49 17224652
2018 Mutant p63 Affects Epidermal Cell Identity through Rewiring the Enhancer Landscape. Cell reports 47 30566872
2007 Transcriptional programs regulated by p63 in normal epithelium and tumors. Cell cycle (Georgetown, Tex.) 47 17297308
2006 p63 overexpression induces the expression of Sonic Hedgehog. Molecular cancer research : MCR 47 17050669
2005 Expression of p63 in diffuse large B-cell lymphoma. Applied immunohistochemistry & molecular morphology : AIMM 47 16082248
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2007 Expression of p63 in thymomas and normal thymus. American journal of clinical pathology 43 17276940
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2005 Expression of p63 and p73 in ameloblastomas. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 40 15752257
2006 p63: a new link between senescence and aging. Cell cycle (Georgetown, Tex.) 39 16434880
2001 CUSP/p63 expression in rat and human tissues. Journal of dermatological science 39 11532371
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2009 Copper-GHK increases integrin expression and p63 positivity by keratinocytes. Archives of dermatological research 31 19319546
2009 P63 (CKAP4) as an SP-A receptor: implications for surfactant turnover. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 31 20054143
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1991 Reconstitution and properties of homologous and chimeric HIV-1.HIV-2 p66.p51 reverse transcriptase. The Journal of biological chemistry 30 1720776
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