TP63

Tumor protein p63

C-terminal domain of the p63 protein
PDB rendering based on 1rg6.

Available structures
PDB	1RG6, 2RMN

Identifiers

Symbols

TP63; AIS; B(p51A); B(p51B); EEC3; KET; LMS; NBP; OFC8; RHS; SHFM4; TP53CP; TP53L; TP73L; p40; p51; p53CP; p63; p73H; p73L

External IDs

OMIM: 603273 MGI: 1330810 HomoloGene: 31189 GeneCards: TP63 Gene

Gene Ontology
Molecular function	• p53 binding • DNA binding • chromatin binding • damaged DNA binding • double-stranded DNA binding • sequence-specific DNA binding transcription factor activity • protein binding • protein domain specific binding • identical protein binding • sequence-specific DNA binding • metal ion binding
Cellular component	• chromatin • nucleus • nucleus • transcription factor complex • nucleolus • cytoplasm • Golgi apparatus • cytosol • rough microsome • dendrite
Biological process	• negative regulation of transcription from RNA polymerase II promoter • replicative cell aging • skeletal system development • establishment of planar polarity • positive regulation of mesenchymal cell proliferation • epithelial cell development • transcription, DNA-dependent • apoptosis • anti-apoptosis • induction of apoptosis • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator • spermatogenesis • pattern specification process • ectoderm and mesoderm interaction • organ morphogenesis • proximal/distal pattern formation • response to X-ray • multicellular organismal aging • response to gamma radiation • embryonic limb morphogenesis • prostate gland development • polarized epithelial cell differentiation • hair follicle morphogenesis • mitotic cell cycle G1/S transition DNA damage checkpoint • cellular response to UV • tail morphogenesis • odontogenesis of dentine-containing tooth • DNA damage response, signal transduction by p53 class mediator resulting in induction of apoptosis • regulation of neuron apoptosis • skin morphogenesis • keratinocyte proliferation • negative regulation of keratinocyte differentiation • positive regulation of Notch signaling pathway • negative regulation of transcription, DNA-dependent • positive regulation of transcription, DNA-dependent • positive regulation of transcription, DNA-dependent • positive regulation of transcription from RNA polymerase II promoter • sympathetic nervous system development • anatomical structure formation involved in morphogenesis • smooth muscle tissue development • female genitalia morphogenesis • protein homotetramerization • urinary bladder development • cloacal septation • prostatic bud formation • squamous basal epithelial stem cell differentiation involved in prostate gland acinus development
Sources: Amigo / QuickGO

RNA expression pattern

More reference expression data

Orthologs

Species

Human

Mouse

RefSeq (mRNA)

RefSeq (protein)

Location (UCSC)

Chr 3:
189.35 – 189.62 Mb

Chr 16:
25.68 – 25.89 Mb

PubMed search

[1]

[2]

Tumor protein p63 also known as transformation-related protein 63 is a protein that in humans is encoded by the TP63 gene.^[1]^[2]^[3]^[4]

TP63 also known as the p63 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.^[5] 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.^[6]

1 Function
2 Clinical significance
3 Diagnostic utility
4 Interactions
5 Regulation
6 See also
7 References
8 Further reading
9 External links

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.^[7] In contrast, TAp63 has been mostly restricted to its apoptotic function and more recently as the guardian of oocyte integrity.^[8] Recently, two new functions have been attributed to TAp63 in heart development^[9] and premature aging.^[10]

Clinical significance

Mutations in the TP63 gene are associated with ectrodactyly-ectodermal dysplasia-cleft syndrome, Hay–Wells syndrome, cleft lip/palate syndrome 3 (EEC3); split-hand/foot malformation 4 (SHFM4); ankyloblepharon-ectodermal defects-cleft lip/palate; ADULT syndrome (acro-dermato-ungual-lacrimal-tooth); limb-mammary syndrome; Rap-Hodgkin syndrome (RHS); and orofacial cleft 8.

Diagnostic utility

p63 immunostaining has utility for differentiating prostatic adenocarcinoma (the most common type of prostate cancer) and benign prostatic tissue;^[11] normal prostatic glands stain with p63 (as they have basal cells), while the malignant glands in prostatic adenocarcinoma (which lacks these cells) do not.^[12] 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.^[13]

Interactions

TP63 has been shown to interact with HNRPAB.^[14]

Regulation

There is some evidence that the expression of p63 is regulated by the microRNA miR-203.^[15]^[16]

References

^ Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, Andrews NC, Caput D, McKeon F (September 1998). "p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities". Mol. Cell 2 (3): 305–16. doi:10.1016/S1097-2765(00)80275-0. PMID 9774969.
^ Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, Ikawa Y, Nimura Y, Nakagawara A, Obinata M, Ikawa S (July 1998). "Cloning and functional analysis of human p51, which structurally and functionally resembles p53". Nat. Med. 4 (7): 839–43. doi:10.1038/nm0798-839. PMID 9662378.
^ Zeng X, Zhu Y, Lu H (February 2001). "NBP is the p53 homolog p63". Carcinogenesis 22 (2): 215–9. doi:10.1093/carcin/22.2.215. PMID 11181441.
^ Tan M, Bian J, Guan K, Sun Y (February 2001). "p53CP is p51/p63, the third member of the p53 gene family: partial purification and characterization". Carcinogenesis 22 (2): 295–300. doi:10.1093/carcin/22.2.295. PMID 11181451.
^ Wu G, Nomoto S, Hoque MO, Dracheva T, Osada M, Lee CC, Dong SM, Guo Z, Benoit N, Cohen Y, Rechthand P, Califano J, Moon CS, Ratovitski E, Jen J, Sidransky D, Trink B (May 2003). "DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development". Cancer Res. 63 (10): 2351–7. PMID 12750249.
^ Skipper M (January 2007). "Dedicated protection for the female germline". Nature Reviews Molecular Cell Biology 8 (1): 4–5. doi:10.1038/nrm2091.
^ Crum CP, McKeon FD (2010). "p63 in epithelial survival, germ cell surveillance, and neoplasia". Annu Rev Pathol 5: 349–71. doi:10.1146/annurev-pathol-121808-102117. PMID 20078223.
^ Deutsch GB, Zielonka EM, Coutandin D, Weber TA, Schäfer B, Hannewald J, Luh LM, Durst FG, Ibrahim M, Hoffmann J, Niesen FH, Sentürk A, Kunkel H, Brutschy B, Schleiff E, Knapp S, Acker-Palmer A, Grez M, McKeon F, Dötsch V (February 2011). "DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer". Cell 144 (4): 566–76. doi:10.1016/j.cell.2011.01.013. PMC 3087504. PMID 21335238. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3087504.
^ Rouleau M, Medawar A, Hamon L, Shivtiel S, Wolchinsky Z, Zhou H, De Rosa L, Candi E, de la Forest Divonne S, Mikkola ML, van Bokhoven H, Missero C, Melino G, Pucéat M, Aberdam D (September 2011). "TAp63 is Important for Cardiac Differentiation of Embryonic Stem Cells and Heart Development". Stem Cells 29: 1612–1683. doi:10.1002/stem.723. PMID 21898690. http://minus.com/lNWTY9g2q5yYG.
^ Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER (July 2009). "TAp63 prevents premature aging by promoting adult stem cell maintenance". Cell Stem Cell 5 (1): 64–75. doi:10.1016/j.stem.2009.04.003. PMID 19570515.
^ Shiran MS, Tan GC, Sabariah AR, Rampal L, Phang KS (March 2007). "p63 as a complementary basal cell specific marker to high molecular weight-cytokeratin in distinguishing prostatic carcinoma from benign prostatic lesions". Med. J. Malaysia 62 (1): 36–9. PMID 17682568.
^ Herawi M, Epstein JI (June 2007). "Immunohistochemical antibody cocktail staining (p63/HMWCK/AMACR) of ductal adenocarcinoma and Gleason pattern 4 cribriform and noncribriform acinar adenocarcinomas of the prostate". Am. J. Surg. Pathol. 31 (6): 889–94. doi:10.1097/01.pas.0000213447.16526.7f. PMID 17527076.
^ Zhang H, Liu J, Cagle PT, Allen TC, Laga AC, Zander DS (January 2005). "Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach". Mod. Pathol. 18 (1): 111–8. doi:10.1038/modpathol.3800251. PMID 15309021.
^ Fomenkov A, Huang YP, Topaloglu O, Brechman A, Osada M, Fomenkova T et al. (2003). "P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome.". J Biol Chem 278 (26): 23906–14. doi:10.1074/jbc.M300746200. PMID 12692135.
^ Yi R, Poy MN, Stoffel M, Fuchs E (March 2008). "A skin microRNA promotes differentiation by repressing 'stemness'". Nature 452 (7184): 225–9. doi:10.1038/nature06642. PMID 18311128.
^ Aberdam D, Candi E, Knight RA, Melino G (December 2008). "miRNAs, 'stemness' and skin". Trends Biochem. Sci. 33 (12): 583–91. doi:10.1016/j.tibs.2008.09.002. PMID 18848452. http://min.us/lGvvAc29SY8ux.

External links

PDB gallery

1rg6: Solution structure of the C-terminal domain of p63

Neoplasm: Tumor suppressor genes/proteins and Oncogenes/Proto-oncogenes

Ligand

Growth factors	ONCO: c-Sis/PDGF · HGF

Receptor

Wnt signaling pathway	TSP: CDH1

Hedgehog signaling pathway	TSP: PTCH1

TGF beta signaling pathway	TSP: TGF beta receptor 2

Receptor tyrosine kinase	ONCO: ErbB/c-ErbB (HER2/neu, Her 3) - c-Met - c-Ret

JAK-STAT signaling pathway	ONCO: c-Kit - Flt3

Intracellular signaling P+Ps

Wnt signaling pathway	ONCO: Beta-catenin · TSP: APC

TGF beta signaling pathway	TSP: SMAD2, SMAD4

Akt/PKB signaling pathway	TSP: PTEN · ONCO: c-Akt

Hippo signaling pathway	TSP: Neurofibromin 2/Merlin

MAPK/ERK pathway	TSP: Neurofibromin 1 · ONCO: c-Ras/HRAS, c-Raf

Other/unknown	TSP: Maspin · ONCO: c-Src

Nucleus

Cell cycle	TSP: p53 · pRb · WT1 · p16/p14arf · ONCO: CDK4 · Cyclin D · Cyclin E

DNA repair/Fanconi	ONCO: BRCA1 - BRCA2

Ubiquitin ligase	TSP: VHL · ONCO: CBL - MDM2

Transcription factor	TSP: KLF6 · ONCO: AP-1 (c-Fos, c-Jun) - c-Myc

Mitochondria

Apoptosis inhibitor: SDHB - SDHD

Other/ungrouped

c-Bcl-2 - Notch - Stathmin

M: NEO

tsoc, mrkr

tumr, epon, para

drug (L1i/1e/V03)

Transcription factors and intracellular receptors

(1) Basic domains

(1.1) Basic leucine zipper (bZIP)	Activating transcription factor (AATF, 1, 2, 3, 4, 5, 6, 7) · AP-1 (c-Fos, FOSB, FOSL1, FOSL2, JDP2, c-Jun, JUNB, JUND) · BACH (1, 2) · BATF · BLZF1 · C/EBP (α, β, γ, δ, ε, ζ) · CREB (1, 3, L1) · CREM · DBP · DDIT3 · GABPA · HLF · MAF (B, F, G, K) · NFE (2, L1, L2, L3) · NFIL3 · NRL · NRF (1, 2, 3) · XBP1

(1.2) Basic helix-loop-helix (bHLH)	ATOH1 · AhR · AHRR · ARNT · ASCL1 · BHLHB2 · BMAL (ARNTL, ARNTL2) · CLOCK · EPAS1 · FIGLA · HAND (1, 2) · HES (5, 6) · HEY (1, 2, L) · HES1 · HIF (1A, 3A) · ID (1, 2, 3, 4) · LYL1 · MESP2 · MXD4 · MYCL1 · MYCN · Myogenic regulatory factors (MyoD, Myogenin, MYF5, MYF6) · Neurogenins (1, 2, 3) · NeuroD (1, 2) · NPAS (1, 2, 3) · OLIG (1, 2) · Pho4 · Scleraxis · SIM (1, 2) · TAL (1, 2) · Twist · USF1

(1.3) bHLH-ZIP	AP-4 · MAX · MITF · MNT · MLX · MXI1 · Myc · SREBP (1, 2)

(1.4) NF-1	NFI (A, B, C, X) · SMAD (R-SMAD (1, 2, 3, 5, 9) - I-SMAD (6, 7) - 4)

(1.5) RF-X	RFX (1, 2, 3, 4, 5, ANK)

(1.6) Basic helix-span-helix (bHSH)	AP-2 (α, β, γ, δ, ε)

(2) Zinc finger DNA-binding domains

(2.1) Nuclear receptor (Cys₄)	subfamily 1 (Thyroid hormone (α, β), CAR, FXR, LXR (α, β), PPAR (α, β/δ, γ), PXR, RAR (α, β, γ), ROR (α, β, γ), Rev-ErbA (α, β), VDR) subfamily 2 (COUP-TF (I, II), Ear-2, HNF4 (α, γ), PNR, RXR (α, β, γ), Testicular receptor (2, 4), TLX) subfamily 3 (Steroid hormone (Androgen, Estrogen (α, β), Glucocorticoid, Mineralocorticoid, Progesterone), Estrogen related (α, β, γ)) subfamily 4 NUR (NGFIB, NOR1, NURR1) · subfamily 5 (LRH-1, SF1) · subfamily 6 (GCNF) · subfamily 0 (DAX1, SHP)

(2.2) Other Cys₄	GATA (1, 2, 3, 4, 5, 6) · MTA (1, 2, 3) · TRPS1

(2.3) Cys₂His₂	General transcription factors (TFIIA, TFIIB, TFIID, TFIIE (1, 2), TFIIF (1, 2), TFIIH (1, 2, 4, 2I, 3A, 3C1, 3C2)) ATBF1 · BCL (6, 11A, 11B) · CTCF · E4F1 · EGR (1, 2, 3, 4) · ERV3 · GFI1 · GLI-Krüppel family (1, 2, 3, REST, S2, YY1) · HIC (1, 2) · HIVEP (1, 2, 3) · IKZF (1, 2, 3) · ILF (2, 3) · KLF (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17) · MTF1 · MYT1 · OSR1 · PRDM9 · SALL (1, 2, 3, 4) · SP (1, 2, 4, 7, 8) · TSHZ3 · WT1 · Zbtb7 (7A, 7B) · ZBTB (16, 17, 20, 32, 33, 40) · zinc finger (3, 7, 9, 10, 19, 22, 24, 33B, 34, 35, 41, 43, 44, 51, 74, 143, 146, 148, 165, 202, 217, 219, 238, 239, 259, 267, 268, 281, 295, 300, 318, 330, 346, 350, 365, 366, 384, 423, 451, 452, 471, 593, 638, 644, 649, 655)

(2.4) Cys₆	HIVEP1

(2.5) Alternating composition	AIRE · DIDO1 · GRLF1 · ING (1, 2, 4) · JARID (1A, 1B, 1C, 1D, 2) · JMJD1B

(3) Helix-turn-helix domains

(3.1) Homeodomain	ARX · CDX (1, 2) · CRX · CUTL1 · DBX (1, 2) · DLX (3, 4, 5) · EMX2 · EN (1, 2) · FHL (1, 2, 3) · HESX1 · HHEX · HLX · Homeobox (A1, A2, A3, A4, A5, A7, A9, A10, A11, A13, B1, B2, B3, B4, B5, B6, B7, B8, B9, B13, C4, C5, C6, C8, C9, C10, C11, C12, C13, D1, D3, D4, D8, D9, D10, D11, D12, D13) · HOPX · IRX (1, 2, 3, 4, 5, 6, MKX) · LMX (1A, 1B) · MEIS (1, 2) · MEOX2 · MNX1 · MSX (1, 2) · NANOG · NKX (2-1, 2-2, 2-3, 2-5, 3-1, 3-2, 6-1, 6-2) · NOBOX · PBX (1, 2, 3) · PHF (1, 3, 6, 8, 10, 16, 17, 20, 21A) · PHOX (2A, 2B) · PITX (1, 2, 3) · POU domain (PIT-1, BRN-3: A, B, C, Octamer transcription factor: 1, 2, 3/4, 6, 7, 11) · OTX (1, 2) · PDX1 · SATB2 · SHOX2 · VAX1 · ZEB (1, 2)

(3.2) Paired box	PAX (1, 2, 3, 4, 5, 6, 7, 8, 9)

(3.3) Fork head / winged helix	E2F (1, 2, 3, 4, 5) · FOX proteins (A1, A2, A3, C1, C2, D3, D4, E1, E3, F1, G1, H1, I1, J1, J2, K1, K2, L2, M1, N1, N3, O1, O3, O4, P1, P2, P3, P4)

(3.4) Heat Shock Factors	HSF (1, 2, 4)

(3.5) Tryptophan clusters	ELF (2, 4, 5) · EGF · ELK (1, 3, 4) · ERF · ETS (1, 2, ERG, SPIB) · ETV (1, 4, 5, 6) · FLI1 · Interferon regulatory factors (1, 2, 3, 4, 5, 6, 7, 8) · MYB · MYBL2

(3.6) TEA domain	transcriptional enhancer factor (1, 2, 3, 4)

(4) β-Scaffold factors with minor groove contacts

(4.1) Rel homology region	NF-κB (NFKB1, NFKB2, REL, RELA, RELB) · NFAT (C1, C2, C3, C4, 5)

(4.2) STAT	STAT (1, 2, 3, 4, 5, 6)

(4.3) p53	p53 · TBX (1, 2, 3, 5, 19, 21, 22, Brachyury, TBR1, TBR2) · TP63

(4.4) MADS box	Mef2 (A, B, C, D) · SRF

(4.6) TATA binding proteins	TBP · TBPL1

(4.7) High-mobility group	BBX · HMGB (1, 2, 3, 4) · HMGN (1, 2, 3, 4) · HNF (1A, 1B) · LEF1 · SOX (1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 18, 21) · SRY · SSRP1 · TCF (3, 4) · TOX (1, 2, 3, 4)

(4.10) Cold-shock domain	CSDA, YBX1

(4.11) Runt	CBF (CBFA2T2, CBFA2T3, RUNX1, RUNX2, RUNX3, RUNX1T1)

(0) Other transcription factors

(0.2) HMGI(Y)	HMGA (1, 2) · HBP1

(0.3) Pocket domain	Rb · RBL1 · RBL2

(0.5) AP-2/EREBP-related factors	Apetala 2 · EREBP · B3

(0.6) Miscellaneous	ARID (1A, 1B, 2, 3A, 3B, 4A) · CAP · IFI (16, 35) · MLL (2, 3, T1) · MNDA · NFY (A, B, C) · Rho/Sigma

see also transcription factor/coregulator deficiencies
B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)

Cell cycle proteins

Cyclin

A (A1, A2) · B (B1, B2, B3) · D (D1, D2, D3) · E (E1, E2)

CDK

2 · 3 · 4 · 5 · 6 · 7 · 8 · 9 · 10 · CDK-activating kinase

CDK inhibitor

INK4a/ARF (p14arf/p16, p15, p18, p19) · cip/kip (p21, p27, p57)

P53 p63 p73 family

p53 · p63 · p73

Phases and
checkpoints

Interphase	G₁ phase · S phase · G₂ phase

M phase	Mitosis (Preprophase · Prophase · Prometaphase · Metaphase · Anaphase · Telophase) · Cytokinesis

Cell cycle checkpoints	Restriction point · Spindle checkpoint · Postreplication checkpoint

Other cellular phases	Apoptosis · G₀ phase · Meiosis

B bsyn: dna (repl, cycl, reco, repr) · tscr (fact, tcrg, nucl, rnat, rept, ptts) · tltn (risu, pttl, nexn) · dnab, rnab/runp · stru (domn, 1°, 2°, 3°, 4°)