TP63

Tumor protein p63

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

Available structures

Ortholog search: PDBe, RCSB

List of PDB id codes
1RG6, 2RMN, 2Y9T, 2Y9U, 3QYM, 3QYN, 3US0, 3US1, 3US2, 3ZY0, 3ZY1, 4A9Z

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	• RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription • p53 binding • DNA binding • chromatin binding • damaged DNA binding • double-stranded DNA binding • sequence-specific DNA binding transcription factor activity • protein binding • identical protein binding • sequence-specific DNA binding • transcription regulatory region DNA binding • metal ion binding
Cellular component	• chromatin • nuclear chromatin • nucleus • nucleoplasm • transcription factor complex • nucleolus • cytoplasm • Golgi apparatus • cytosol • dendrite
Biological process	• negative regulation of transcription from RNA polymerase II promoter • skeletal system development • establishment of planar polarity • positive regulation of mesenchymal cell proliferation • epithelial cell development • chromatin remodeling • apoptotic process • induction of apoptosis • DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator • Notch signaling pathway • ectoderm and mesoderm interaction • cell aging • proximal/distal pattern formation • response to X-ray • multicellular organismal aging • response to gamma radiation • keratinocyte differentiation • embryonic limb morphogenesis • polarized epithelial cell differentiation • hair follicle morphogenesis • mitotic cell cycle G1/S transition DNA damage checkpoint • cellular response to UV • odontogenesis of dentin-containing tooth • intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator • regulation of neuron apoptotic process • skin morphogenesis • keratinocyte proliferation • negative regulation of keratinocyte differentiation • positive regulation of osteoblast differentiation • positive regulation of Notch signaling pathway • negative regulation of transcription, DNA-dependent • positive regulation of transcription, DNA-dependent • positive regulation of transcription from RNA polymerase II promoter • sympathetic nervous system development • smooth muscle tissue development • female genitalia morphogenesis • 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
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

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]

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

TP63 mutations underlie several malformation syndromes that include cleft lip and/or palate as a hallmark feature.^[11] Mutations in the TP63 gene are associated with ectrodactyly-ectodermal dysplasia-cleft syndrome in which a midline cleft lip is a common feature,^[11] 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,^[11] 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.^[11] Recently, induced pluripotent stem cells have be produced from patients affected by EEC syndromes by cell reprogramming. The defective epithelial commitment could be partially rescued by a small therapeutic compound.^[12]

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;^[13] normal prostatic glands stain with p63 (as they have basal cells), while the malignant glands in prostatic adenocarcinoma (which lacks these cells) do not.^[14] 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.^[15]

Interactions

TP63 has been shown to interact with HNRPAB.^[16] It also activates IRF6 transcription through the IRF6 enhancer element.^[11]

Regulation

There is some evidence that the expression of p63 is regulated by the microRNA miR-203.^[17]^[18]

References

↑ Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, Andrews NC, Caput D, McKeon F (Sep 1998). "p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities". Molecular 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 (Jul 1998). "Cloning and functional analysis of human p51, which structurally and functionally resembles p53". Nature Medicine 4 (7): 839–43. doi:10.1038/nm0798-839. PMID 9662378.
↑ Zeng X, Zhu Y, Lu H (Feb 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 (Feb 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 Research 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". Annual Review of Pathology 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 (Feb 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.
↑ 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 (Nov 2011). "TAp63 is important for cardiac differentiation of embryonic stem cells and heart development". Stem Cells 29 (11): 1672–83. doi:10.1002/stem.723. PMID 21898690.
↑ Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, Biernaskie JA, Sinha S, Prives C, Pevny LH, Miller FD, Flores ER (Jul 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. PMC 3418222. PMID 19570515.
1 2 3 4 5 Dixon MJ, Marazita ML, Beaty TH, Murray JC (Mar 2011). "Cleft lip and palate: understanding genetic and environmental influences". Nature Reviews. Genetics 12 (3): 167–78. doi:10.1038/nrg2933. PMC 3086810. PMID 21331089.
↑ Shalom Feuerstein R. et al. Impaired epithelial differentiation of induced pluripotent stem cells from EEC patients is rescued by APR-246/PRIMA-1MET. P.N.A.S 2012. http://minus.com/lbmC3TVGDx350s
↑ Shiran MS, Tan GC, Sabariah AR, Rampal L, Phang KS (Mar 2007). "p63 as a complimentary basal cell specific marker to high molecular weight-cytokeratin in distinguishing prostatic carcinoma from benign prostatic lesions". The Medical Journal of Malaysia 62 (1): 36–9. PMID 17682568.
↑ Herawi M, Epstein JI (Jun 2007). "Immunohistochemical antibody cocktail staining (p63/HMWCK/AMACR) of ductal adenocarcinoma and Gleason pattern 4 cribriform and noncribriform acinar adenocarcinomas of the prostate". The American Journal of Surgical Pathology 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 (Jan 2005). "Distinction of pulmonary small cell carcinoma from poorly differentiated squamous cell carcinoma: an immunohistochemical approach". Modern Pathology 18 (1): 111–8. doi:10.1038/modpathol.3800251. PMID 15309021.
↑ Fomenkov A, Huang YP, Topaloglu O, Brechman A, Osada M, Fomenkova T, Yuriditsky E, Trink B, Sidransky D, Ratovitski E (Jun 2003). "P63 alpha mutations lead to aberrant splicing of keratinocyte growth factor receptor in the Hay-Wells syndrome". The Journal of Biological Chemistry 278 (26): 23906–14. doi:10.1074/jbc.M300746200. PMID 12692135.
↑ Yi R, Poy MN, Stoffel M, Fuchs E (Mar 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 (Dec 2008). "miRNAs, 'stemness' and skin". Trends in Biochemical Sciences 33 (12): 583–91. doi:10.1016/j.tibs.2008.09.002. PMID 18848452.

External links

TP73L protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
GeneReviews/NCBI/NIH/UW entry on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome or AEC Syndrome, Hay-Wells Syndrome. Includes: Rapp-Hodgkin Syndrome
OMIM entries on AEC
TP63 human gene location in the UCSC Genome Browser.
TP63 human gene details in the UCSC Genome Browser.

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	TSP: BRCA1 BRCA2

Ubiquitin ligase	TSP: VHL ONCO: CBL MDM2

Transcription factor	TSP: KLF6 ONCO: AP-1 c-Fos c-Jun c-Myc

Mitochondrion

Other/ungrouped

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 BHLH 2 3 9 ARNTL 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 MXD3 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 6 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
- S1
- S2
- YY1
HIC
- 1
- 2
HIVEP
- 1
- 2
- 3
IKZF
- 1
- 2
- 3
ILF
- 2
- 3
KLF
- 1
- 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
- 11
- 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

(2.6) WRKY

WRKY

(3) Helix-turn-helix domains

(3.1) Homeodomain	ARX CDX 1 2 CRX CUTL1 DBX 1 2 DLX 3 4 5 EMX 1 2 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 SIX 1 2 3 4 5 VAX1 ZEB 1 2

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

(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 TBR1 TBR2 TFT MYRF 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

(4.9) Grainyhead	TFCP2

(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

Cell cycle proteins

Cyclin

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

CDK

CDK inhibitor

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

P53 p63 p73 family

Other

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

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