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TP63 (tumor protein p63)

Written2012-12Austin Mattox, Zhong Chen, Carter Van Waes
Clinical Genomics Unit, Tumor Biology Section, Head, Neck Surgery Branch, National Institute on Deafness, Other Communication Disorders, NIH, Bethesda, MD, 20892, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesTP73L
TP53L
TP53CP
tumor protein p73-like
tumor protein p53-like
tumor protein p53-competing protein
Alias_symbol (synonym)p51
SHFM4
EEC3
p63
p73L
OFC8
KET
p73H
NBP
p53CP
Other aliasAIS
B(p51A)
B(p51B)
LMS
RHS
p40
HGNC (Hugo) TP63
LocusID (NCBI) 8626
Atlas_Id 365
Location 3q28  [Link to chromosome band 3q28]
Location_base_pair Starts at 189631427 and ends at 189897279 bp from pter ( according to hg19-Feb_2009)  [Mapping TP63.png]
Fusion genes
(updated 2016)		B3GALNT1 (3q26.1) / TP63 (3q28)GABARAPL2 (16q23.1) / TP63 (3q28)IL1RAP (3q28) / TP63 (3q28)
LPP (3q28) / TP63 (3q28)MAN2B2 (4p16.1) / TP63 (3q28)P3H2 (3q28) / TP63 (3q28)
TBL1XR1 (3q26.32) / TP63 (3q28)TMEM110 (3p21.1) / TP63 (3q28)TNRC6B (22q13.1) / TP63 (3q28)
TP63 (3q28) / MVK (12q24.11)TP63 (3q28) / TBL1XR1 (3q26.32)ZMAT3 (3q26.32) / TP63 (3q28)

DNA/RNA

Note Human TP63 was first isolated from human total genomic DNA by screening with an 800 bp PCR fragment obtained from probing with primers designed to anneal to regions in contiguous exons of p53 and p73, including the intervening introns (Yang et al., 1998). The resulting clones recovered from SK-N-MC neuroepithelioma total genomic DNA encoded proteins with two different N termini (TA and ΔN) and five different C termini (α, β, γ, δ, and ε; figure 1) (Yang et al., 1998; Mangiulli et al., 2009). Short splicing isoforms lacking exon 4 have been observed in invasive breast carcinomas (de Biase et al., 2010) that are not presented in figure 1.
Description The TP63 gene spans 267 kb, contains 16 exons, encodes 680 amino acids for the longest isoform, and has 12 isoforms formed by alternative promoter usage and alternative splicing (Augustin et al., 1998; Muzny et al., 2006; Parsons et al., 2009; Vanbokhoven et al., 2011). The six variants with TA and ΔN at the N-terminal and α, β, γ at the C-terminal are the most known and studied isoforms.

Protein

 
  Figure 1. The Human TP63 isoforms. A) Human TAp63 and ΔNp63 with α, β, γ, δ, ε splice variant protein isoforms are shown. TP63 protein functional domains are depicted. TA: transactivation domain; ΔN: N-terminally truncated isoform; DBD: DNA binding domain; OD: oligomerization domain; the second TA domain; SAM: sterile alpha motif; ID: inhibitory domain. B) Exon schema and corresponding domains of the human TP63 gene. Alternative promoter use produces TA (transactivation) and N-terminally truncated (ΔN) isoforms, and alternative splicing produces C-terminal variants. Alternatively spliced forms of exon 10 are designated as 10* and 10**.
Description Human TP63 encodes the p63 protein, of which the longest isoform contains 680 amino acids, has molecular weights ranging from 44 to 77 kDa, depending on specific alternative promoter usage and alternative splicing (Augustin et al., 1998; Yang et al., 1998). TP63 comprises up to five types of domains, depending on the isoform, and may contain transactivation (TA), DNA Binding (DBD), oligomerization (OD), C-terminal sterile alpha motif (SAM), and/or C-terminal transcription inhibitory (ID) domains (Moll and Slade, 2004). The N-terminus may consist of a TA domain or a truncated version (ΔN) lacking the acidic TA domain that is derived from an alternative promoter and initiation codon in intron 3 (Yang et al., 1998). The 3' end of both TAp63 and ΔNp63 may be alternatively spliced to yield isoforms α, β, γ, and δ, while the ε-isoform is formed from transcriptional termination in exon 10 (Mangiulli et al., 2009). TAp63α and ΔNp63α contain a protein-protein interaction SAM domain and a trans-inhibitory domain, resulting from the masking of N-terminal TA domain residues. The δ- and ε-isoform proteins are formed by transcriptional termination in the second TA domain and after the OD, respectively (Mangiulli et al., 2009) (figure 1).

Structure
TP63 binds DNA as either a homo- or a heterotetramer, with isoform composition of the tetramer possibly determining transactivation activity. p63 may also form mixed dimers or tetramers with p73 at relatively higher affinity than with p53, suggesting functional cross talk to regulate transcriptional activity (Davison et al., 1999; Natan and Joerger, 2012). p63 appears to form a dimer of dimers, with monomers consisting of a β-strand followed by two helices (H1 and H2) that adopt a z-shaped double-hairpin conformation with little intramolecular contact between structural elements (Natan and Joerger, 2012). Monomers dimerize via intermolecular antiparallel β-sheet interactions and antiparallel packing of the H1 helices, with important hydrophobic contacts made by key leucine, valine, tyrosine, methionine, and isoleucine residues (Natan and Joerger, 2012). Tetramers are formed by hydrophobic H1-H1 interactions and H2-mediated contact where the H2 helices from the primary dimer clasps the adjacent dimer, packing the tetramer in an orthogonal fashion via H1 helices arrangement (Natan and Joerger, 2012). Analysis of the DBD of TP63 shows higher similarity to that of p73 than p53, and appears to bind a 10-bp DNA sequence containing a "CATG" motif with A/T-rich flanking regions (Chen et al., 2011).

Expression TP63 expression is found in fetal and adult tissues, including the skin, cervix, vaginal epithelium, urothelium, prostate, heart, testis, kidney, thymus, brain, and spleen (Yang et al., 1998). Immunohistochemistry of p63 often shows strong nuclear-localized staining in basal epithelial cells. Additionally, TA and ΔN isoforms appear to be differentially expressed in particular tissue types. TAp63 variants are prevalent in the heart, testis, kidney, thymus, brain, and cerebellum. ΔNp63 transcripts are detected heavily in epithelial cells, kidney, spleen, and thymus, but not in the heart, liver, testis, or brain (Yang et al., 1998; Dötsch et al., 2010).
Localisation As a transcription factor, p63 is normally present in the nucleus (Yang et al., 1998).
Function TP63 acts as a motif-specific transcriptional activator or repressor, depending on the presence of TA or ID domains in the specific p63 isoform (Yang et al., 1998). It plays a critical role in the maintenance of progenitor-cell populations that encourage epithelial development and morphogenesis (Romano et al., 2009). ΔNp63, once thought to serve as a dominant negative regulator due to its lack of a full TA domain, has recently been implicated in transcriptionally activating and repressing target genes such as Keratin 5 and Keratin 14 to dictate early epithelial development and determine keratinocyte cell fate and lineage choices (Yang et al., 1998; Romano et al., 2009). Less is known about TAp63 function. Mice with germline deletion of TAp63 display blisters, decreased hair morphogenesis, and potential maintenance of adult stem cells, though full characterization of TAp63 function is lacking (Su et al., 2009).
While the interactomes of TP53 and TP73 have been systematically analyzed and cataloged, until recently, no such information had been compiled for TP63 (Tozluoglu et al., 2008; Collavin et al., 2010). Recent protein chip analysis has elucidated 144 proteins that specifically interact with TP63 and are implicated in cell growth/death/survival, chromatin remodeling and gene regulation, RNA processing, protein trafficking and degradation, and other and epithelial differentiation (Huang et al., 2012). A representative protein and its function from each of the aforementioned categories are described below, while a complete list may be found in the supplemental data of Huang et al. (2012).
Cell growth/survival: Signal Transducer and Activator of Transcription 3 (STAT3) - STAT3 is a latent cytoplasmic transcription factor activated in response to various interleukins and growth factors that binds the promoter regions of IL-6-induced plasma protein and intermediate-early genes (Akira et al., 1994; McLoughlin et al., 2005; Huang et al., 2012).
Chromatin remodeling: SWI/SNF Regulator of Chromatin 1 (SMARCC1) - SMARCC1 is a component of the larger SWI/SNF complex responsible for chromatin remodeling necessary for transcriptional activation of certain genes (Wang et al., 1996; Ring et al., 1998; Huang et al., 2012).
Gene regulation/expression: Eukaryotic Translation Initiation Factor 4A2 (EIF4A2) - EIF4A2 plays an important role in the binding of mRNA to the 43S pre-initiation complex during the beginning of protein synthesis (Sudo et al., 1995; Huang et al., 2012).
RNA processing: Splicing Factor 3b, Subunit 4 (SF3B4) - SF3B4 interacts with other spliceosome proteins to help cross-link a 29-nucleotide region in the pre-mRNA near the branch-point sequence in the A complex (Champion-Arnaud and Reed, 1994; Huang et al., 2012).
Protein trafficking: Trafficking Protein Particle Complex 2-Like (TRAPPC2L) - TRAPPC2L is part of the TRAPP multi-subunit tethering complex involved in intracellular vesicle trafficking (Scrivens et al., 2011; Huang et al., 2012).
Protein degradation: Ubiquitin Conjugation Factor E4 B Isoform 1 (UFD2A) - UFD2A has been shown to promote monoubiquitination of p53 and, in combination with MDM2, to promote p53 polyubiquitination (Wu and Leng, 2011; Wu et al., 2011; Huang et al., 2012).
Epithelial differentiation: Keratin 1 (KRT1) - KRT1 is a marker for terminal differentiation in the mammalian epidermis (Lessin et al., 1988; Huang et al., 2012).
Through protein-protein interactions with other transcription and cofactors, TP63 also contributes to the transcriptional regulation of genes involved in cellular differentiation, proliferation/survival, growth suppression, apoptosis, adhesion, inflammation, and metabolism (Perez and Pietenpol, 2007; Viganò and Mantovani, 2007; Yang et al., 2011). Recent work by our laboratory has identified protein-protein interactions between ΔNp63α, TAp73, and c-REL that function to regulate key genes involved in growth arrest and apoptosis of mutant p53 head and neck squamous cell carcinoma (HNSCC) (Lu et al., 2011). Functionally important genes representing each of the aforementioned categories are described below, while more comprehensive reviews may be found in Perez and Pietenpol (2007) and Viganò and Mantovani (2007).
Cellular differentiation: Jagged 1 (JAG1) - JAG1 is the ligand of the Notch receptor. It's binding causes a proteolytic cleavage cascade, leading to translocation of the intracellular component of the Notch receptor and subsequent activation of transcription factors with key roles in cell differentiation and morphogenesis (Gray et al., 1999; Sasaki et al., 2002; Guarnaccia et al., 2004). Overexpression of p63γ has been shown to dramatically upregulate JAG1 protein levels in colorectal cancer, osteogenic sarcoma, lung cancer, hepatocellular carcinoma, and glioma (Sasaki et al., 2002).
Proliferation/survival: Epidermal Growth Factor Receptor (EGFR) - EGFR is the receptor for epidermal growth factor and is involved in modulating cellular functions such as cell proliferation, differentiation, and survival by activating various intracellular signaling cascades such as RAS and STAT that transcribe target genes important in cellular proliferation and survival (Carpenter, 1984; Jamnongjit et al., 2005; Testoni et al., 2006). Knockdown of ΔNp63α has been shown to reduce expression of EGFR in keratinocytes (Testoni et al., 2006).
Growth suppression: Cyclin-Dependent Kinase Inhibitor 1A (CDKN1A) - CDKN1A (p21) associates with cyclins A, D, and E to prevent the G1-S phase transition in mammals (el-Deiry et al., 1993; Westfall et al., 2003). Overexpression of ΔNp63α has been shown to reduce expression of p21 in HEK cells (Westfall et al., 2003).
Apoptosis: p53-Upregulated Modulator of Apoptosis (PUMA) - PUMA binds to BCL2 to induce rapid and profound apoptosis by cytochrome c release (Yu et al., 2001; Flores et al., 2002). Additionally, recent work has shown that a complex of ΔNp63α, with TAp73 or c-REL, can modify expression of key growth arrest and apoptotic genes such as p21WAF1, NOXA, and PUMA (Lu et al., 2011; Yang et al., 2011).
Adhesion: Integrin Alpha 6 (ITGA6) - ITGA6 is a cell surface adhesion molecule that may help regulate migration and layer formation, especially in epithelial cells. Mouse models deficient in ITGA6 display severe blistering of the skin and other epithelia and die shortly after birth (Georges-Labouesse et al., 1996; Carroll et al., 2006). Loss of endogenous p63 in mammary epithelial cells has been shown to induce detachment and cell death, presumably because p63 regulates expression of key adhesion molecules such as ITGA6, ITGB1, ITGB4 other ECM components, and cadherins-catenins (Carroll et al., 2006; Yang et al., 2011).
Inflammation: ΔNp63 overexpression has been observed in head and neck squamous cell carcinoma (HNSCC), which are associated with inflammation. TNF-α, a potent pro-inflammatory cytokine, promoted NF-κB, c-REL and RELA complexes with nuclear ΔNp63, to promote a broad-spectrum production of cytokines and chemokines (Lu et al., 2011; Yang et al., 2011). In addition, in squamous epithelia of ΔNp63α transgenic mice, severe inflammation, skin lesions and erythema were observed after ΔNp63 expression was induced. Microscopically, hyperplastic and hyperproliferative epidermis with diffuse infiltration of inflammatory cells in the dermis was observed (Yang et al., 2011). NF-κB family proteins, c-Rel and RelA, and numerous inflammatory cytokines and chemokines were significantly upregulated in ΔNp63 transgenic mice.
Metabolism: Fatty Acid Synthase (FASN) - FASN catalyzes the conversion of Acetyl-CoA and Malonyl-CoA into long-chain saturated fatty acids with the help of NADPH (Wakil, 1989; D'Erchia et al., 2006). ΔNp63α (and TAp73α) expression has also been shown to induce promoter and enhancer activity in human FASN gene by binding to p53 response elements (D'Erchia et al., 2006).
Mouse models TP63 knockout mice are born alive but have striking developmental defects including absent or truncated limbs, lack of stratified epithelia, and lack hair follicles, teeth, and mammary glands. Thus, TP63 is essential for epidermal-mesenchymal interactions during embryonic development, including regenerative limb proliferation, craniofacial and epithelial development, and differentiation of squamous epithelia (Yang et al., 1998; Mills et al., 1999; McKeon, 2004; Laurikkala et al., 2006). Recently, ΔNp63α transgenic mice have been developed using tissue-specific tetracycline inducible expression. Mice expressing ΔNp63α under a tissue-specific promoter (SPC) for lung epithelium exhibited Keratin 5 and 14 induction, trans-differentiation to an epidermal cell lineage, and squamous metaplasia. Overexpression of ΔNp63α under a K5 promoter in wild-type epidermis results in severe defects in hair follicle development and cycling, leading to severe hair loss and a depleted hair follicle stem-cell niche (Romano et al., 2009; Romano et al., 2010). In addition, ΔNp63α overexpression induced marked skin inflammation, and skin hyperplasia (Yang et al., 2011). A more detailed summary of the phenotypes of different p63 knockout and transgenic mouse models has recently been published (Vanbokhoven et al., 2011).
Homology In addition to humans, the TP63 gene is conserved in chimpanzees, dogs, cows, mice, rats, chicken, and zebrafish, and evolutionary precursors have been detected in Cnidarians.

Implicated in

Note
  
Entity Various cancers
Note Genome-wide association studies and in vivo work have identified TP63 mutations and/or overexpression in multiple cancers, including lung, bladder, esophageal, and head and neck squamous cell carcinoma (Rocco et al., 2006; Rothman et al., 2010; Hu et al., 2011; Stransky et al., 2011; Yang et al., 2011; Ellinghaus et al., 2012). While these studies have correlated certain mutations with an increased risk for cancer, the molecular effects of these mutations are not as well characterized as those in the aforementioned autosomal dominant disorders. Immunohistochemistry (IHC) in head and neck squamous cell carcinoma (HNSCC) has identified overexpression of TP63 isoforms in the majority of tumor specimens. Although the tumorigenic effect of all the TP63 isoforms has yet to be fully understood, unregulated TP63 expression is an early pathogenic event in HNSCC and inhibition of TP63 can induce apoptotic cell death (Westfall and Pietenpol, 2004; Chen et al., 2005; Rocco et al., 2006). Additionally, ΔNp63α has been shown to increase the half-life of hypoxia-inducible factor 1α, leading to upregulation of vascular endothelial growth factor (VEGF) expression in vitro in human non-small cell carcinoma cell lines (Senoo et al., 2002). Transcriptional activation of matrix metalloproteases (MMPs) has also been seen with high levels of ΔNp63α (Patturajan et al., 2002; Hildesheim et al., 2004). TAp73/ΔNp63α interaction has also been shown to mediate chemosensitivity to cisplatin in primary breast cancers (Leong et al., 2007). More recently, ΔNp63 overexpression is shown in HNSCC to correlate with increased epithelial inflammation, proliferation, and migration by regulating gene programs important in cancer progression (Yang et al., 2011). In addition, TNF-α, a potent pro-inflammatory cytokine, promoted c-REL translocation and complexes with nuclear ΔNp63, while TAp73 dissociated from ΔNp63 and the promoters of key growth arrest and apoptosis genes p21CIP1/WAF1, NOXA, and PUMA. Increased nuclear ΔNp63α was detected in human HNSCC tumors, and hyperplastic squamous epithelia of transgenic mice overexpressing ΔNp63α (Lu et al., 2011). Such a novel mechanism explains how inflammation activates proto-oncogenic NF-κB and overcomes TP53/p63/p73 family mediated tumor suppression. Furthermore, it has been found that ΔNp63α interacts with IκB kinases, and IKKβ promotes ubiquitin-mediated proteasomal degradation of ΔNp63α. Conversely, IKKβ inhibition attenuated cytokine- or chemotherapy-induced degradation of ΔNp63α (Chatterjee et al., 2010).
  
  
Entity Acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome
Note ADULT syndrome may be caused by heterozygous mutations in the TP63 gene, including missense mutations R298Q and R227Q. Features include ectrodactyly, syndactyly, finger and toenail dysplasia, hypoplastic breasts and nipples, freckling, lacrimal duct atresia, frontal alopecia, primary hypodontia, and loss of permanent teeth (Reisler et al., 2006; Rinne et al., 2006).
  
  
Entity Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (EEC3)
Note EEC3 is an autosomal dominant disorder caused by a heterozygous mutation in TP63, most likely in the DNA-binding domain. Clinically, EEC3 presents with absence of the central parts of the hands and feet, resulting in split-hand/foot malformations, ectodermal dysplasia, and cleft lip that may or may not include cleft palate (Maas et al., 1996; Akahoshi et al., 2003).
  
  
Entity Hay-Wells syndrome
Note While similar to phenotype to ADULT syndrome and EEC3, Hay-Wells syndrome is caused by a heterozygous mutation in TP63 in the sterile alpha motif (SAM) domain. Hay-Wells Syndrome is characterized by congenital ectodermal dysplasia with course, sparse hair, dystrophic nails, scalp infections, hypodontia, maxillary hypoplasia, and cleft lip/palate (Hay and Wells, 1976; McGrath et al., 2001).
  
  
Entity Limb-mammary syndrome (LMS)
Note LMS is caused by a heterozygous mutation in the TP63 gene and is allelic to ADULT syndrome. Features of LMS include severe hand/food anomalies and hypoplasia/aplasia of the mammary gland and nipples (Propping and Zerres, 1993; van Bokhoven et al., 2001).
  

To be noted

Acknowledgements: supported by NIDCD Intramural Project ZIA-DC-000073 and 74.

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Nature. 2006 Apr 27;440(7088):1194-8.
PMID 16641997
 
Structure and kinetic stability of the p63 tetramerization domain.
Natan E, Joerger AC.
J Mol Biol. 2012 Jan 20;415(3):503-13. doi: 10.1016/j.jmb.2011.11.007. Epub 2011 Nov 12.
PMID 22100306
 
Comprehensive mutational analysis and mRNA isoform quantification of TP63 in normal and neoplastic human prostate cells.
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Prostate. 2009 Apr 1;69(5):559-69. doi: 10.1002/pros.20904.
PMID 19142959
 
DeltaNp63 induces beta-catenin nuclear accumulation and signaling.
Patturajan M, Nomoto S, Sommer M, Fomenkov A, Hibi K, Zangen R, Poliak N, Califano J, Trink B, Ratovitski E, Sidransky D.
Cancer Cell. 2002 May;1(4):369-79.
PMID 12086851
 
Transcriptional programs regulated by p63 in normal epithelium and tumors.
Perez CA, Pietenpol JA.
Cell Cycle. 2007 Feb 1;6(3):246-54. Epub 2007 Feb 3.
PMID 17297308
 
ADULT-syndrome: an autosomal-dominant disorder with pigment anomalies, ectrodactyly, nail dysplasia, and hypodontia.
Propping P, Zerres K.
Am J Med Genet. 1993 Mar 1;45(5):642-8.
PMID 8456838
 
Further phenotypic and genetic variation in ADULT syndrome.
Reisler TT, Patton MA, Meagher PP.
Am J Med Genet A. 2006 Nov 15;140(22):2495-500.
PMID 17041931
 
Five SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) genes are dispersed in the human genome.
Ring HZ, Vameghi-Meyers V, Wang W, Crabtree GR, Francke U.
Genomics. 1998 Jul 1;51(1):140-3.
PMID 9693044
 
Delineation of the ADULT syndrome phenotype due to arginine 298 mutations of the p63 gene.
Rinne T, Spadoni E, Kjaer KW, Danesino C, Larizza D, Kock M, Huoponen K, Savontaus ML, Aaltonen M, Duijf P, Brunner HG, Penttinen M, van Bokhoven H.
Eur J Hum Genet. 2006 Aug;14(8):904-10. Epub 2006 May 17.
PMID 16724007
 
p63 mediates survival in squamous cell carcinoma by suppression of p73-dependent apoptosis.
Rocco JW, Leong CO, Kuperwasser N, DeYoung MP, Ellisen LW.
Cancer Cell. 2006 Jan;9(1):45-56.
PMID 16413471
 
An active role of the DeltaN isoform of p63 in regulating basal keratin genes K5 and K14 and directing epidermal cell fate.
Romano RA, Ortt K, Birkaya B, Smalley K, Sinha S.
PLoS One. 2009 May 20;4(5):e5623. doi: 10.1371/journal.pone.0005623.
PMID 19461998
 
A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.
Rothman N, Garcia-Closas M, Chatterjee N, Malats N, Wu X, Figueroa JD, Real FX, Van Den Berg D, Matullo G, Baris D, Thun M, Kiemeney LA, Vineis P, De Vivo I, Albanes D, Purdue MP, Rafnar T, Hildebrandt MA, Kiltie AE, Cussenot O, Golka K, Kumar R, Taylor JA, Mayordomo JI, Jacobs KB, Kogevinas M, Hutchinson A, Wang Z, Fu YP, Prokunina-Olsson L, Burdett L, Yeager M, Wheeler W, Tardon A, Serra C, Carrato A, Garcia-Closas R, Lloreta J, Johnson A, Schwenn M, Karagas MR, Schned A, Andriole G Jr, Grubb R 3rd, Black A, Jacobs EJ, Diver WR, Gapstur SM, Weinstein SJ, Virtamo J, Cortessis VK, Gago-Dominguez M, Pike MC, Stern MC, Yuan JM, Hunter DJ, McGrath M, Dinney CP, Czerniak B, Chen M, Yang H, Vermeulen SH, Aben KK, Witjes JA, Makkinje RR, Sulem P, Besenbacher S, Stefansson K, Riboli E, Brennan P, Panico S, Navarro C, Allen NE, Bueno-de-Mesquita HB, Trichopoulos D, Caporaso N, Landi MT, Canzian F, Ljungberg B, Tjonneland A, Clavel-Chapelon F, Bishop DT, Teo MT, Knowles MA, Guarrera S, Polidoro S, Ricceri F, Sacerdote C, Allione A, Cancel-Tassin G, Selinski S, Hengstler JG, Dietrich H, Fletcher T, Rudnai P, Gurzau E, Koppova K, Bolick SC, Godfrey A, Xu Z, Sanz-Velez JI, D Garcia-Prats M, Sanchez M, Valdivia G, Porru S, Benhamou S, Hoover RN, Fraumeni JF Jr, Silverman DT, Chanock SJ.
Nat Genet. 2010 Nov;42(11):978-84. doi: 10.1038/ng.687. Epub 2010 Oct 24.
PMID 20972438
 
The p53 family member genes are involved in the Notch signal pathway.
Sasaki Y, Ishida S, Morimoto I, Yamashita T, Kojima T, Kihara C, Tanaka T, Imai K, Nakamura Y, Tokino T.
J Biol Chem. 2002 Jan 4;277(1):719-24. Epub 2001 Oct 18.
PMID 11641404
 
C4orf41 and TTC-15 are mammalian TRAPP components with a role at an early stage in ER-to-Golgi trafficking.
Scrivens PJ, Noueihed B, Shahrzad N, Hul S, Brunet S, Sacher M.
Mol Biol Cell. 2011 Jun 15;22(12):2083-93. doi: 10.1091/mbc.E10-11-0873. Epub 2011 Apr 27.
PMID 21525244
 
TAp63gamma (p51A) and dNp63alpha (p73L), two major isoforms of the p63 gene, exert opposite effects on the vascular endothelial growth factor (VEGF) gene expression.
Senoo M, Matsumura Y, Habu S.
Oncogene. 2002 Apr 11;21(16):2455-65.
PMID 11971180
 
The mutational landscape of head and neck squamous cell carcinoma.
Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A, Kryukov GV, Lawrence MS, Sougnez C, McKenna A, Shefler E, Ramos AH, Stojanov P, Carter SL, Voet D, Cortes ML, Auclair D, Berger MF, Saksena G, Guiducci C, Onofrio RC, Parkin M, Romkes M, Weissfeld JL, Seethala RR, Wang L, Rangel-Escareno C, Fernandez-Lopez JC, Hidalgo-Miranda A, Melendez-Zajgla J, Winckler W, Ardlie K, Gabriel SB, Meyerson M, Lander ES, Getz G, Golub TR, Garraway LA, Grandis JR.
Science. 2011 Aug 26;333(6046):1157-60. doi: 10.1126/science.1208130. Epub 2011 Jul 28.
PMID 21798893
 
TAp63 prevents premature aging by promoting adult stem cell maintenance.
Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER.
Cell Stem Cell. 2009 Jul 2;5(1):64-75. doi: 10.1016/j.stem.2009.04.003.
PMID 19570515
 
Isolation and mapping of the human EIF4A2 gene homologous to the murine protein synthesis initiation factor 4A-II gene Eif4a2.
Sudo K, Takahashi E, Nakamura Y.
Cytogenet Cell Genet. 1995;71(4):385-8.
PMID 8521730
 
Identification of new p63 targets in human keratinocytes.
Testoni B, Borrelli S, Tenedini E, Alotto D, Castagnoli C, Piccolo S, Tagliafico E, Ferrari S, Vigano MA, Mantovani R.
Cell Cycle. 2006 Dec;5(23):2805-11. Epub 2006 Dec 1.
PMID 17172858
 
Cataloging and organizing p73 interactions in cell cycle arrest and apoptosis.
Tozluoglu M, Karaca E, Haliloglu T, Nussinov R.
Nucleic Acids Res. 2008 Sep;36(15):5033-49. doi: 10.1093/nar/gkn481. Epub 2008 Jul 26.
PMID 18660513
 
p63, a story of mice and men.
Vanbokhoven H, Melino G, Candi E, Declercq W.
J Invest Dermatol. 2011 Jun;131(6):1196-207. doi: 10.1038/jid.2011.84. Epub 2011 Apr 7.
PMID 21471985
 
Hitting the numbers: the emerging network of p63 targets.
Vigano MA, Mantovani R.
Cell Cycle. 2007 Feb 1;6(3):233-9. Epub 2007 Feb 3.
PMID 17297297
 
Fatty acid synthase, a proficient multifunctional enzyme.
Wakil SJ.
Biochemistry. 1989 May 30;28(11):4523-30.
PMID 2669958
 
Diversity and specialization of mammalian SWI/SNF complexes.
Wang W, Xue Y, Zhou S, Kuo A, Cairns BR, Crabtree GR.
Genes Dev. 1996 Sep 1;10(17):2117-30.
PMID 8804307
 
p63: Molecular complexity in development and cancer.
Westfall MD, Pietenpol JA.
Carcinogenesis. 2004 Jun;25(6):857-64. Epub 2004 Mar 19.
PMID 15033906
 
UBE4B, a ubiquitin chain assembly factor, is required for MDM2-mediated p53 polyubiquitination and degradation.
Wu H, Leng RP.
Cell Cycle. 2011 Jun 15;10(12):1912-5. Epub 2011 Jun 15.
PMID 21558803
 
UBE4B promotes Hdm2-mediated degradation of the tumor suppressor p53.
Wu H, Pomeroy SL, Ferreira M, Teider N, Mariani J, Nakayama KI, Hatakeyama S, Tron VA, Saltibus LF, Spyracopoulos L, Leng RP.
Nat Med. 2011 Mar;17(3):347-55. doi: 10.1038/nm.2283. Epub 2011 Feb 13.
PMID 21317885
 
p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.
Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V, Andrews NC, Caput D, McKeon F.
Mol Cell. 1998 Sep;2(3):305-16.
PMID 9774969
 
DeltaNp63 versatilely regulates a Broad NF-kB gene program and promotes squamous epithelial proliferation, migration, and inflammation.
Yang X, Lu H, Yan B, Romano RA, Bian Y, Friedman J, Duggal P, Allen C, Chuang R, Ehsanian R, Si H, Sinha S, Van Waes C, Chen Z.
Cancer Res. 2011 May 15;71(10):3688-700. doi: 10.1158/0008-5472.CAN-10-3445.
PMID 21576089
 
PUMA induces the rapid apoptosis of colorectal cancer cells.
Yu J, Zhang L, Hwang PM, Kinzler KW, Vogelstein B.
Mol Cell. 2001 Mar;7(3):673-82.
PMID 11463391
 
p63 short isoforms are found in invasive carcinomas only and not in benign breast conditions.
de Biase D, Morandi L, Degli Esposti R, Ligorio C, Pession A, Foschini MP, Eusebi V.
Virchows Arch. 2010 Apr;456(4):395-401. doi: 10.1007/s00428-010-0900-1. Epub 2010 Mar 12.
PMID 20225093
 
WAF1, a potential mediator of p53 tumor suppression.
el-Deiry WS, Tokino T, Velculescu VE, Levy DB, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW, Vogelstein B.
Cell. 1993 Nov 19;75(4):817-25.
PMID 8242752
 
p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation.
van Bokhoven H, Hamel BC, Bamshad M, Sangiorgi E, Gurrieri F, Duijf PH, Vanmolkot KR, van Beusekom E, van Beersum SE, Celli J, Merkx GF, Tenconi R, Fryns JP, Verloes A, Newbury-Ecob RA, Raas-Rotschild A, Majewski F, Beemer FA, Janecke A, Chitayat D, Crisponi G, Kayserili H, Yates JR, Neri G, Brunner HG.
Am J Hum Genet. 2001 Sep;69(3):481-92. Epub 2001 Jul 17.
PMID 11462173
 

Citation

This paper should be referenced as such :
Mattox, A ; Chen, Z ; Van, Waes C
TP63 (tumor protein p63)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(6):414-420.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/TP63ID365ch3q27.html

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  Anaplastic large cell lymphoma, ALK-negative

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 5 ]
  Head and Neck: Squamous cell carcinoma: an overview
Head and Neck: Epidermoid carcinoma
Lung: Non-small cell carcinoma
Squamous cell cancer
Lung: Translocations in Squamous Cell Carcinoma

External links

Nomenclature
HGNC (Hugo)TP63   15979
LRG (Locus Reference Genomic)LRG_428
Cards
AtlasTP63ID365ch3q27
Entrez_Gene (NCBI)TP63  8626  tumor protein p63
AliasesAIS; B(p51A); B(p51B); EEC3; 
KET; LMS; NBP; OFC8; RHS; SHFM4; TP53CP; TP53L; TP73L; p40; p51; p53CP; p63; p73H; p73L
GeneCards (Weizmann)TP63
Ensembl hg19 (Hinxton)ENSG00000073282 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000073282 [Gene_View]  chr3:189631427-189897279 [Contig_View]  TP63 [Vega]
ICGC DataPortalENSG00000073282
TCGA cBioPortalTP63
AceView (NCBI)TP63
Genatlas (Paris)TP63
WikiGenes8626
SOURCE (Princeton)TP63
Genetics Home Reference (NIH)TP63
Genomic and cartography
GoldenPath hg38 (UCSC)TP63  -     chr3:189631427-189897279 +  3q28   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)TP63  -     3q28   [Description]    (hg19-Feb_2009)
EnsemblTP63 - 3q28 [CytoView hg19]  TP63 - 3q28 [CytoView hg38]
Mapping of homologs : NCBITP63 [Mapview hg19]  TP63 [Mapview hg38]
OMIM103285   106260   129400   603273   603543   604292   605289   
Gene and transcription
Genbank (Entrez)AB010153 AB016072 AB016073 AB042841 AF075428
RefSeq transcript (Entrez)NM_001114978 NM_001114979 NM_001114980 NM_001114981 NM_001114982 NM_001329144 NM_001329145 NM_001329146 NM_001329148 NM_001329149 NM_001329150 NM_001329964 NM_003722
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)TP63
Cluster EST : UnigeneHs.137569 [ NCBI ]
CGAP (NCI)Hs.137569
Alternative Splicing GalleryENSG00000073282
Gene ExpressionTP63 [ NCBI-GEO ]   TP63 [ EBI - ARRAY_EXPRESS ]   TP63 [ SEEK ]   TP63 [ MEM ]
Gene Expression Viewer (FireBrowse)TP63 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8626
GTEX Portal (Tissue expression)TP63
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9H3D4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9H3D4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9H3D4
Splice isoforms : SwissVarQ9H3D4
PhosPhoSitePlusQ9H3D4
Domaine pattern : Prosite (Expaxy)P53 (PS00348)   
Domains : Interpro (EBI)p53-like_TF_DNA-bd    p53/RUNT-type_TF_DNA-bd    p53_DNA-bd    p53_tetrameristn    p53_tumour_suppressor    SAM    SAM/pointed    Tp63   
Domain families : Pfam (Sanger)P53 (PF00870)    P53_tetramer (PF07710)    SAM_2 (PF07647)   
Domain families : Pfam (NCBI)pfam00870    pfam07710    pfam07647   
Domain families : Smart (EMBL)SAM (SM00454)  
Conserved Domain (NCBI)TP63
DMDM Disease mutations8626
Blocks (Seattle)TP63
PDB (SRS)1RG6    2NB1    2RMN    2Y9T    2Y9U    3QYM    3QYN    3US0    3US1    3US2    3ZY0    3ZY1    4A9Z   
PDB (PDBSum)1RG6    2NB1    2RMN    2Y9T    2Y9U    3QYM    3QYN    3US0    3US1    3US2    3ZY0    3ZY1    4A9Z   
PDB (IMB)1RG6    2NB1    2RMN    2Y9T    2Y9U    3QYM    3QYN    3US0    3US1    3US2    3ZY0    3ZY1    4A9Z   
PDB (RSDB)1RG6    2NB1    2RMN    2Y9T    2Y9U    3QYM    3QYN    3US0    3US1    3US2    3ZY0    3ZY1    4A9Z   
Structural Biology KnowledgeBase1RG6    2NB1    2RMN    2Y9T    2Y9U    3QYM    3QYN    3US0    3US1    3US2    3ZY0    3ZY1    4A9Z   
SCOP (Structural Classification of Proteins)1RG6    2NB1    2RMN    2Y9T    2Y9U    3QYM    3QYN    3US0    3US1    3US2    3ZY0    3ZY1    4A9Z   
CATH (Classification of proteins structures)1RG6    2NB1    2RMN    2Y9T    2Y9U    3QYM    3QYN    3US0    3US1    3US2    3ZY0    3ZY1    4A9Z   
SuperfamilyQ9H3D4
Human Protein AtlasENSG00000073282
Peptide AtlasQ9H3D4
HPRD04469
IPIIPI00301360   IPI00514871   IPI00514017   IPI00513733   IPI00514298   IPI00514155   IPI00514665   IPI00184272   IPI00514961   IPI00514807   IPI00479019   IPI00514384   IPI00922485   IPI00925120   
Protein Interaction databases
DIP (DOE-UCLA)Q9H3D4
IntAct (EBI)Q9H3D4
FunCoupENSG00000073282
BioGRIDTP63
STRING (EMBL)TP63
ZODIACTP63
Ontologies - Pathways
QuickGOQ9H3D4
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  nuclear chromatin  transcription factor activity, transcription factor binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  replicative cell aging  skeletal system development  establishment of planar polarity  p53 binding  p53 binding  positive regulation of mesenchymal cell proliferation  epithelial cell development  DNA binding  chromatin binding  damaged DNA binding  double-stranded DNA binding  transcription factor activity, sequence-specific DNA binding  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  transcription factor complex  cytoplasm  mitochondrion  rough endoplasmic reticulum  Golgi apparatus  cytosol  cytosol  chromatin remodeling  transcription from RNA polymerase II promoter  apoptotic process  DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator  Notch signaling pathway  spermatogenesis  ectoderm and mesoderm interaction  proximal/distal pattern formation  response to X-ray  multicellular organism aging  response to gamma radiation  epidermal cell division  regulation of epidermal cell division  positive regulation of keratinocyte proliferation  keratinocyte differentiation  embryonic limb morphogenesis  dendrite  polarized epithelial cell differentiation  hair follicle morphogenesis  mitotic G1 DNA damage checkpoint  negative regulation of intracellular estrogen receptor signaling pathway  cellular response to UV  post-anal tail morphogenesis  odontogenesis of dentin-containing tooth  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  identical protein binding  regulation of apoptotic process  negative regulation of apoptotic process  regulation of cysteine-type endopeptidase activity involved in apoptotic process  regulation of neuron apoptotic process  sequence-specific DNA binding  skin morphogenesis  keratinocyte proliferation  transcription regulatory region DNA binding  negative regulation of keratinocyte differentiation  positive regulation of osteoblast differentiation  positive regulation of Notch signaling pathway  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  sympathetic nervous system development  smooth muscle tissue development  female genitalia morphogenesis  WW domain binding  protein homotetramerization  neuron apoptotic process  urinary bladder development  cloacal septation  prostatic bud formation  squamous basal epithelial stem cell differentiation involved in prostate gland acinus development  establishment of skin barrier  MDM2/MDM4 family protein binding  positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway  regulation of signal transduction by p53 class mediator  positive regulation of somatic stem cell population maintenance  positive regulation of fibroblast apoptotic process  negative regulation of mesoderm development  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  nuclear chromatin  transcription factor activity, transcription factor binding  transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding  replicative cell aging  skeletal system development  establishment of planar polarity  p53 binding  p53 binding  positive regulation of mesenchymal cell proliferation  epithelial cell development  DNA binding  chromatin binding  damaged DNA binding  double-stranded DNA binding  transcription factor activity, sequence-specific DNA binding  transcription factor activity, sequence-specific DNA binding  protein binding  nucleus  nucleus  nucleoplasm  nucleoplasm  transcription factor complex  cytoplasm  mitochondrion  rough endoplasmic reticulum  Golgi apparatus  cytosol  cytosol  chromatin remodeling  transcription from RNA polymerase II promoter  apoptotic process  DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator  Notch signaling pathway  spermatogenesis  ectoderm and mesoderm interaction  proximal/distal pattern formation  response to X-ray  multicellular organism aging  response to gamma radiation  epidermal cell division  regulation of epidermal cell division  positive regulation of keratinocyte proliferation  keratinocyte differentiation  embryonic limb morphogenesis  dendrite  polarized epithelial cell differentiation  hair follicle morphogenesis  mitotic G1 DNA damage checkpoint  negative regulation of intracellular estrogen receptor signaling pathway  cellular response to UV  post-anal tail morphogenesis  odontogenesis of dentin-containing tooth  intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator  identical protein binding  regulation of apoptotic process  negative regulation of apoptotic process  regulation of cysteine-type endopeptidase activity involved in apoptotic process  regulation of neuron apoptotic process  sequence-specific DNA binding  skin morphogenesis  keratinocyte proliferation  transcription regulatory region DNA binding  negative regulation of keratinocyte differentiation  positive regulation of osteoblast differentiation  positive regulation of Notch signaling pathway  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  metal ion binding  sympathetic nervous system development  smooth muscle tissue development  female genitalia morphogenesis  WW domain binding  protein homotetramerization  neuron apoptotic process  urinary bladder development  cloacal septation  prostatic bud formation  squamous basal epithelial stem cell differentiation involved in prostate gland acinus development  establishment of skin barrier  MDM2/MDM4 family protein binding  positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway  regulation of signal transduction by p53 class mediator  positive regulation of somatic stem cell population maintenance  positive regulation of fibroblast apoptotic process  negative regulation of mesoderm development  
Pathways : KEGGMicroRNAs in cancer   
REACTOMEQ9H3D4 [protein]
REACTOME PathwaysR-HSA-6804759 [pathway]   
NDEx NetworkTP63
Atlas of Cancer Signalling NetworkTP63
Wikipedia pathwaysTP63
Orthology - Evolution
OrthoDB8626
GeneTree (enSembl)ENSG00000073282
Phylogenetic Trees/Animal Genes : TreeFamTP63
HOVERGENQ9H3D4
HOGENOMQ9H3D4
Homologs : HomoloGeneTP63
Homology/Alignments : Family Browser (UCSC)TP63
Gene fusions - Rearrangements
Fusion : MitelmanTBL1XR1/TP63 [3q26.32/3q28]  [inv(3)(q26q28)]  
Fusion : MitelmanTMEM110/TP63 [3p21.1/3q28]  [inv(3)(p21q28)]  
Fusion : MitelmanTP63/TBL1XR1 [3q28/3q26.32]  [inv(3)(q26q28)]  
Fusion : MitelmanZMAT3/TP63 [3q26.32/3q28]  [t(3;3)(q26;q28)]  
Fusion: TCGAIL1RAP 3q28 TP63 3q28 LUSC
Fusion: TCGALEPREL1 TP63 3q28 LGG
Fusion: TCGALPP 3q28 TP63 3q28 BRCA
Fusion: TCGAZMAT3 3q26.32 TP63 3q28 SKCM
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerTP63 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)TP63
dbVarTP63
ClinVarTP63
1000_GenomesTP63 
Exome Variant ServerTP63
ExAC (Exome Aggregation Consortium)TP63 (select the gene name)
Genetic variants : HAPMAP8626
Genomic Variants (DGV)TP63 [DGVbeta]
DECIPHERTP63 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisTP63 
Mutations
ICGC Data PortalTP63 
TCGA Data PortalTP63 
Broad Tumor PortalTP63
OASIS PortalTP63 [ Somatic mutations - Copy number]
Cancer Gene: CensusTP63 
Somatic Mutations in Cancer : COSMICTP63  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDTP63
LOVD (Leiden Open Variation Database)ARVD/C Genetic Variants Database
BioMutasearch TP63
DgiDB (Drug Gene Interaction Database)TP63
DoCM (Curated mutations)TP63 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)TP63 (select a term)
intoGenTP63
NCG5 (London)TP63
Cancer3DTP63(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM103285    106260    129400    603273    603543    604292    605289   
Orphanet1365    1297    1864    2261    10919    12490   
MedgenTP63
Genetic Testing Registry TP63
NextProtQ9H3D4 [Medical]
TSGene8626
GENETestsTP63
Target ValidationTP63
Huge Navigator TP63 [HugePedia]
snp3D : Map Gene to Disease8626
BioCentury BCIQTP63
ClinGenTP63 (curated)
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8626
Chemical/Pharm GKB GenePA162406776
Clinical trialTP63
Miscellaneous
canSAR (ICR)TP63 (select the gene name)
Probes
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineTP63
EVEXTP63
GoPubMedTP63
iHOPTP63
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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