TP63
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4A9Z, 1RG6, 2RMN, 2Y9T, 2Y9U, 3QYM, 3QYN, 3US0, 3US1, 3US2, 3ZY0, 3ZY1
Identifiers
Aliases	TP63, AIS, B(p51A), B(p51B), EEC3, KET, LMS, NBP, OFC8, RHS, SHFM4, TP53CP, TP53L, TP73L, p40, p51, p53CP, p63, p73H, p73L, tumor protein p63
External IDs	OMIM: 603273 MGI: 1330810 HomoloGene: 31189 GeneCards: TP63
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q28 Start 189,631,389 bp[1] End 189,897,276 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16 B1|16 17.37 cM Start 25,502,513 bp[2] End 25,710,852 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in human penis hair follicle vulva gums nipple skin of abdomen oral cavity cervix epithelium body of tongue deltoid muscle Top expressed in hair follicle molar conjunctival fornix skin of back corneal stroma lip superior surface of tongue skin of abdomen esophagus maxillary prominence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA-binding transcription activator activity, RNA polymerase II-specific metal ion binding damaged DNA binding protein binding WW domain binding double-stranded DNA binding DNA binding sequence-specific DNA binding identical protein binding chromatin binding p53 binding DNA-binding transcription factor activity MDM2/MDM4 family protein binding DNA-binding transcription factor activity, RNA polymerase II-specific protein domain specific binding Cellular component cytoplasm neuron projection nucleus rough endoplasmic reticulum transcription regulator complex nucleoplasm dendrite mitochondrion Golgi apparatus cytosol protein-containing complex Biological process pattern specification process skeletal system development epithelial cell development negative regulation of keratinocyte differentiation epidermal cell division anatomical structure formation involved in morphogenesis prostate gland development transcription by RNA polymerase II squamous basal epithelial stem cell differentiation involved in prostate gland acinus development ectoderm and mesoderm interaction cellular response to DNA damage stimulus female genitalia morphogenesis odontogenesis of dentin-containing tooth prostatic bud formation positive regulation of cell cycle G1/S phase transition positive regulation of mesenchymal cell proliferation spermatogenesis multicellular organism aging smooth muscle tissue development positive regulation of fibroblast apoptotic process animal organ morphogenesis hair follicle morphogenesis positive regulation of Notch signaling pathway apoptotic process chromatin remodeling regulation of transcription, DNA-templated regulation of neuron apoptotic process positive regulation of apoptotic signaling pathway regulation of cysteine-type endopeptidase activity involved in apoptotic process transcription, DNA-templated embryonic limb morphogenesis negative regulation of mesoderm development epidermis development post-anal tail morphogenesis response to gamma radiation protein homotetramerization Notch signaling pathway hair follicle development neuron apoptotic process polarized epithelial cell differentiation proximal/distal pattern formation cell differentiation positive regulation of keratinocyte proliferation skin morphogenesis epithelial cell differentiation urinary bladder development cellular response to UV establishment of planar polarity negative regulation of apoptotic process negative regulation of transcription by RNA polymerase II protein tetramerization keratinocyte proliferation positive regulation of osteoblast differentiation regulation of epidermal cell division negative regulation of transcription, DNA-templated negative regulation of cellular senescence intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator sympathetic nervous system development establishment of skin barrier morphogenesis of a polarized epithelium keratinocyte differentiation multicellular organism development mitotic G1 DNA damage checkpoint signaling cloacal septation response to X-ray positive regulation of transcription by RNA polymerase II DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway regulation of signal transduction by p53 class mediator regulation of apoptotic process human ageing negative regulation of intracellular estrogen receptor signaling pathway positive regulation of transcription, DNA-templated positive regulation of somatic stem cell population maintenance cell population proliferation epidermal cell differentiation embryonic forelimb morphogenesis embryonic hindlimb morphogenesis skin epidermis development cranial skeletal system development developmental process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 8626 22061 Ensembl ENSG00000073282 ENSMUSG00000022510 UniProt Q9H3D4 O88898 RefSeq (mRNA) NM_001114978 NM_001114979 NM_001114980 NM_001114981 NM_001114982 NM_003722 NM_001329144 NM_001329145 NM_001329146 NM_001329148 NM_001329149 NM_001329150 NM_001329964 NM_001127259 NM_001127260 NM_001127261 NM_001127262 NM_001127263 NM_001127264 NM_001127265 NM_011641 RefSeq (protein) NP_001108450 NP_001108451 NP_001108452 NP_001108453 NP_001108454 NP_001316073 NP_001316074 NP_001316075 NP_001316077 NP_001316078 NP_001316079 NP_001316893 NP_003713 NP_001120731 NP_001120732 NP_001120733 NP_001120734 NP_001120735 NP_001120736 NP_001120737 NP_035771 Location (UCSC) Chr 3: 189.63 – 189.9 Mb Chr 16: 25.5 – 25.71 Mb PubMed search [3] [4]
Wikidata
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Tumor protein p63, typically referred to as p63, also known as transformation-related protein 63 is a protein that in humans is encoded by the TP63 (also known as the p63) gene.^[5][6][7][8]

The TP63 gene was discovered 20 years after the discovery of the p53 tumor suppressor gene and along with p73 constitutes the p53 gene family based on their structural similarity.^[9] Despite being discovered significantly later than p53, phylogenetic analysis of p53, p63 and p73, suggest that p63 was the original member of the family from which p53 and p73 evolved.^[10]

Function

Tumor protein p63 is a member of the p53 family of transcription factors. p63 -/- mice have several developmental defects which include the lack of limbs and other tissues, such as teeth and mammary glands, which develop as a result of interactions between mesenchyme and epithelium. TP63 encodes for two main isoforms by alternative promoters (TAp63 and ΔNp63). ΔNp63 is involved in multiple functions during skin development and in adult stem/progenitor cell regulation.^[11] In contrast, TAp63 has been mostly restricted to its apoptotic function and more recently as the guardian of oocyte integrity.^[12] Recently, two new functions have been attributed to TAp63 in heart development^[13] and premature aging.^[14]

In mice, p63 is required for normal skin development via direct transcription of the membrane protein PERP. TP63 can also regulate PERP expression with TP53 in human cancer.^[15]

Oocyte integrity

In oocytes, a unique quality control system has evolved that eliminates by apoptosis those oocytes in which chromosomes do not align correctly, or in which chromosomes cannot be repaired.^[16] This monitoring system is conserved from fruit flies and nematodes to humans, and central to this system is the p53 protein family and, in vertebrates in particular, the p63 protein.^[16] Oocytes that are unable to repair DNA double-strand breaks produced during meiosis by the process of homologous recombination are eliminated by apoptosis that is linked to p63.^[16]

Clinical significance

At least 42 disease-causing mutations in this gene have been discovered.^[17] TP63 mutations underlie several malformation syndromes that include cleft lip and/or palate as a hallmark feature.^[18] Mutations in the TP63 gene are associated with ectrodactyly-ectodermal dysplasia-cleft syndrome in which a midline cleft lip is a common feature,^[18] cleft lip/palate syndrome 3 (EEC3); ectrodactyly (also known as split-hand/foot malformation 4 (SHFM4)); ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) or Hay–Wells syndrome in which a midline cleft lip is also a common feature,^[18] Acro–dermato–ungual–lacrimal–tooth syndrome (ADULT); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8.

Both cleft lip with or without a cleft palate and cleft palate only features have been seen to segregate within the same family with a TP63 mutation.^[18] Recently, induced pluripotent stem cells have been produced from patients affected by EEC syndromes by cell reprogramming. The defective epithelial commitment could be partially rescued by a small therapeutic compound.^[19]

Molecular mechanism

Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. In a recent study, researchers used EEC-patient-derived skin keratinocytes carrying heterozygous p63 DNA-binding domain mutations as the cellular model to characterize the global gene regulatory alteration. The epidermal cell identity was compromised in p63 mutant keratinocytes. Besides, p63-binding loss and loss of active enhancers occurs at a genome-wide scale in patient keratinocytes carrying heterozygous EEC mutations. ^[20] Besides, using a multi-omics approach, the deregulated function of DNA loops mediated by p63 and CTCF represents an additional layer to the disease mechanism. It seems that a number of loci nearby epidermal genes were organized into a ‘regulatory chromatin hub’ within the chromatin interactions, mediated by CTCF in epidermal keratinocytes. Such hubs contain multiple connecting DNA loops that require not only CTCF binding that is rather static but also binding of cell type-specific TFs, like p63, for the transcriptional activity. In this model, p63 may be essential to make the DNA loops active in transcription. ^[21]

Vulvar cancer

TP63 has been observed overexpressed in Vulvar Squamous Cell Carcinoma samples, in association with hypermethylation-Induced inactivation of the IRF6 tumor suppressor gene. ^[22] Indeed, mRNA levels of TP63 tested higher in Vulvar cancer samples when compared with those of normal skin and preneoplastic vulvar lesions, thus underscoring an epigenetic cross-link between IRF6 gene and the oncogene TP63. ^[22]

Diagnostic utility

p63 immunostaining has utility for head and neck squamous cell carcinomas, differentiating prostatic adenocarcinoma (the most common type of prostate cancer) and benign prostatic tissue;^[23] the nuclei of the basal cells of normal prostatic glands stain with p63, while the malignant glands in prostatic adenocarcinoma (which lacks these cells) do not.^[24] P63 is also helpful in distinguishing poorly differentiated squamous cell carcinoma from small cell carcinoma or adenocarcinoma. P63 should be strongly stained in poorly differentiated squamous cell, but negative in small cell or adenocarcinoma.^[25]

Cytoplasmic staining on immunohistochemistry is seen in cells with muscle differentiation.^[26]

Interactions

TP63 has been shown to interact with HNRPAB.^[27] It also activates IRF6 transcription through the IRF6 enhancer element.^[18]

Regulation

There is some evidence that the expression of p63 is regulated by the microRNA miR-203^[28][29] and USP28 at protein level ^[30][31]