Tumorski protein p63, obično zvani p63, također poznat i kao protein vezan za transformaciju 63 jest protein koji je kod ljudi kodiran genom TP63 sa hromosoma 3.[5][6][7][8]

TP63
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

4A9Z, 1RG6, 2RMN, 2Y9T, 2Y9U, 3QYM, 3QYN, 3US0, 3US1, 3US2, 3ZY0, 3ZY1

Identifikatori
AliasiTP63
Vanjski ID-jeviOMIM: 603273 MGI: 1330810 HomoloGene: 31189 GeneCards: TP63
Lokacija gena (čovjek)
Hromosom 3 (čovjek)
Hrom.Hromosom 3 (čovjek)[1]
Hromosom 3 (čovjek)
Genomska lokacija za TP63
Genomska lokacija za TP63
Bend3q28Početak189,631,389 bp[1]
Kraj189,897,276 bp[1]
Lokacija gena (miš)
Hromosom 16 (miš)
Hrom.Hromosom 16 (miš)[2]
Hromosom 16 (miš)
Genomska lokacija za TP63
Genomska lokacija za TP63
Bend16 B1|16 17.37 cMPočetak25,502,513 bp[2]
Kraj25,710,852 bp[2]
Obrazac RNK ekspresije




Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific
vezivanje iona metala
oštećeno vezivanje sa DNK
GO:0001948, GO:0016582 vezivanje za proteine
WW domain binding
double-stranded DNA binding
vezivanje sa DNK
sequence-specific DNA binding
vezivanje identičnih proteina
chromatin binding
p53 binding
GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity
MDM2/MDM4 family protein binding
GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific
protein domain specific binding
Ćelijska komponenta citoplazma
neuron projection
jedro
rough endoplasmic reticulum
transcription regulator complex
nukleoplazma
dendrit
mitohondrija
Golđijev aparat
citosol
GO:0009327 makromolekulani kompleks
Biološki proces 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
Spermatogeneza
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
GO:0097285 apoptoza
chromatin remodeling
GO:0009373 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
Ćelijska diferencijacija
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
GO:1901227 negative regulation of transcription by RNA polymerase II
protein tetramerization
keratinocyte proliferation
positive regulation of osteoblast differentiation
regulation of epidermal cell division
GO:0045996 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
GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 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
GO:0010260 starenje
negative regulation of intracellular estrogen receptor signaling pathway
GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated
positive regulation of somatic stem cell population maintenance
Ćelijska proliferacija
epidermal cell differentiation
embryonic forelimb morphogenesis
embryonic hindlimb morphogenesis
skin epidermis development
cranial skeletal system development
GO:0007571 developmental process
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)
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 (bjelančevina)
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

Lokacija (UCSC)Chr 3: 189.63 – 189.9 MbChr 16: 25.5 – 25.71 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Gen TP63 je otkriven 20 godina nakon otkrića p53 tumor supresorskog gena i zajedno sa p73 čini porodicu gena p53, zasnovanu na na njihovoj strukturnoj sličnosti.[9] Iako je otkrivena znatno kasnije od p53, filogenetska analiza p53, p63 i p73 sugerira da je p63 bio originalni član porodice iz koje su evoluirali p53 i p73.[10]

Aminokiselinska sekvenca

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Dužina polipeptidnog lanca je 680 aminokiselina, a molekulska težina Da. 76 785[11]

1020304050
MNFETSRCATLQYCPDPYIQRFVETPAHFSWKESYYRSTMSQSTQTNEFL
SPEVFQHIWDFLEQPICSVQPIDLNFVDEPSEDGATNKIEISMDCIRMQD
SDLSDPMWPQYTNLGLLNSMDQQIQNGSSSTSPYNTDHAQNSVTAPSPYA
QPSSTFDALSPSPAIPSNTDYPGPHSFDVSFQQSSTAKSATWTYSTELKK
LYCQIAKTCPIQIKVMTPPPQGAVIRAMPVYKKAEHVTEVVKRCPNHELS
REFNEGQIAPPSHLIRVEGNSHAQYVEDPITGRQSVLVPYEPPQVGTEFT
TVLYNFMCNSSCVGGMNRRPILIIVTLETRDGQVLGRRCFEARICACPGR
DRKADEDSIRKQQVSDSTKNGDGTKRPFRQNTHGIQMTSIKKRRSPDDEL
LYLPVRGRETYEMLLKIKESLELMQYLPQHTIETYRQQQQQQHQHLLQKQ
TSIQSPSSYGNSSPPLNKMNSMNKLPSVSQLINPQQRNALTPTTIPDGMG
ANIPMMGTHMPMAGDMNGLSPTQALPPPLSMPSTSHCTPPPPYPTDCSIV
SFLARLGCSSCLDYFTTQGLTTIYQIEHYSMDDLASLKIPEQFRHAIWKG
ILDHRQLHEFSSPSHLLRTPSSASTVSVGSSETRGERVIDAVRFTLRQTI
SFPPRDEWNDFNFDMDARRNKQQRIKEEGE

Funkcija

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Tumorski protein p63 je član porodice transkripcijskih faktora p53. Miševi p63 –/– imaju nekoliko razvojnih defekata koji uključuju nedostatak udova i drugih tkiva, kao što su zubi i mliječne žlijezde, koji se razvijaju kao posljedica interakcije između mezenhim i epitel a. TP63 kodira dvije glavne izoforme pomoću alternativnih promotora (TAp63 i ΔNp63). ΔNp63 je uključen u višestruke funkcije tokom razvoja kože i u regulaciju matičnih/progenitornih ćelija odraslih.[12] Nasuprot tome, TAp63 je uglavnom bio ograničen na svoju apoptotsku funkciju, a u novije vrijeme i kao čuvar integriteta oocita.[13] Nedavno su TAp63 pripisane dvije nove funkcije u razvoju srca [14] i preranom starenju.[15]

Kod miševa, p63 je neophodan za normalan razvoj kože putem direktne transkripcije membranskog proteina PERP. TP63 također može regulirati ekspresiju PERP sa TP53 kod ljudskog kancera.[16]

Klinički značaj

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Mutacije TP63 su u osnovi nekoliko sindromskih malformacija koje uključuju rascjep usne i/ili nepca kao karakterističnu osobinu.[17] Mutacije u TP63 genu su povezane sa ektrodaktilno-ektodermnom displazijom sindroma rascjepa kod kojeg je rascjep usne po sredini uobičajena karakteristika,[17] uz sindrom rascjepa usne/nepca 3 (EEC3); ektodaktilija (takođe poznata kao malformacija podijeljene šake/stopala 4 (SHFM4)), ankiloblefaron-ektodermna displazija-rascjep usne/nepca (AEC) ili Hay-Wellsov sindrom kod kojih je rascjep usne po sredini također uobičajena oznaka,[17] Acro–dermato–ungual– suzno-zubni sindrom (odraslih); sindrom udova i dojke; Rap-Hodgkinov sindrom (RHS) i orofacijalni rascjep 8.

 
p63 bojenje na tkivu raka prostate korištenjem klonskojg antitijela IHC063

Uočeno je je da se i rascjep usne sa ili bez rascjepa nepca i samo rascjep nepca segregiraju unutar iste porodice s mutacijom TP63.[17] Nedavno su proizvedene inducirane pluripotentne matične ćelije pacijenata pogođenih EEC sindromima, reprogramiranjem ćelija. Defektna vezanost epitela može se djelimično spasiti malim terapeutskim spojem.[18]

Rak vulve

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Uočeno je da je TP63 prekomjerno eksprimiran u uzorcima karcinom vulvnih pločastih ćelija, u vezi sa inaktivacijom gena za supresor tumora, izazvanom hipermetilacijom IRF6.[19] Odista, nivoi iRNK TP63 testirani su u uzorcima raka vulve, u poređenju sa onima normalne kože i preneoplazijskih lezija vulve, čime se naglašava epigenetička unakrsna veza između gena IRF6 i onkogena TP63.[19]

Dijagnostičkinamjenskii program

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Imunobojenje p63 koristi se za karcinome skvamoznih ćelija glave i vrata, diferencirajući adenokarcinom (najčešći tip karcinoma prostate) i benigno tkivo prostate;[20] normalne žlijezde prostate obojene su p63 (jer imaju bazne ćelije), dok maligne žlijezde u adenokarcinomu prostate (kome nedostaju ove ćelije) nemaju.[21] P63 je također od pomoći u razlikovanju slabo diferenciranog karcinoma pločastih ćelija karcinoma malih ćelijkac ili adenokarcinoma. P63 treba biti jako obojen u slabo diferenciranim pločastim, ali negativan u malim ćelijama ili adenokarcinomu.[22]

Interakcije

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Pokazalo se da je TP63 u interakciji sa HNRPAB.[23] Također aktivira transkripciju IRF6 preko elementa pojačivača IRF6.[17]

Regulacija

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Postoje neki dokazi da ekspresiju p63 regulira mikroRNK miR-203[24][25] i USP28.

Postoje neki dokazi da ekspresiju p63 reguliše mikroRNA miR-203 na razini proteina.[26][27]

Također pogledajte

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Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000073282 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022510 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dötsch V, et al. (septembar 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.
  6. ^ Osada M, Ohba M, Kawahara C, Ishioka C, Kanamaru R, Katoh I, et al. (juli 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. S2CID 21953916.
  7. ^ Zeng X, Zhu Y, Lu H (februar 2001). "NBP is the p53 homolog p63". Carcinogenesis. 22 (2): 215–9. doi:10.1093/carcin/22.2.215. PMID 11181441.
  8. ^ Tan M, Bian J, Guan K, Sun Y (februar 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.
  9. ^ Wu G, Nomoto S, Hoque MO, Dracheva T, Osada M, Lee CC, et al. (maj 2003). "DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development". Cancer Research. 63 (10): 2351–7. PMID 12750249.
  10. ^ Skipper M (januar 2007). "Dedicated protection for the female germline". Nature Reviews Molecular Cell Biology. 8 (1): 4–5. doi:10.1038/nrm2091. S2CID 10702219.
  11. ^ "UniProt, Q9H3D4" (jezik: engleski). Pristupljeno 1. 11. 2021.
  12. ^ 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.
  13. ^ Deutsch GB, Zielonka EM, Coutandin D, Weber TA, Schäfer B, Hannewald J, et al. (februar 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.
  14. ^ Rouleau M, Medawar A, Hamon L, Shivtiel S, Wolchinsky Z, Zhou H, et al. (novembar 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. S2CID 40628077. Arhivirano s originala, 8. 8. 2014.
  15. ^ Su X, Paris M, Gi YJ, Tsai KY, Cho MS, Lin YL, et al. (juli 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.
  16. ^ Roberts O, Paraoan L (Dec 2020). "PERP-ing into diverse mechanisms of cancer pathogenesis: Regulation and role of the p53/p63 effector PERP". Biochim Biophys Acta Rev Cancer. 1874 (1): 188393. doi:10.1016/j.bbcan.2020.188393. PMID 32679166. S2CID 220631324.
  17. ^ a b c d e Dixon MJ, Marazita ML, Beaty TH, Murray JC (mart 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.
  18. ^ Shalom-Feuerstein R, Serror L, Aberdam E, Müller FJ, van Bokhoven H, Wiman KG, et al. (februar 2013). "Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET". Proceedings of the National Academy of Sciences of the United States of America. 110 (6): 2152–6. doi:10.1073/pnas.1201753109. PMC 3568301. PMID 23355677.
  19. ^ a b Rotondo JC, Borghi A, Selvatici R, Magri E, Bianchini E, Montinari E, et al. (august 2016). "Hypermethylation-Induced Inactivation of the IRF6 Gene as a Possible Early Event in Progression of Vulvar Squamous Cell Carcinoma Associated With Lichen Sclerosus". JAMA Dermatology. 152 (8): 928–33. doi:10.1001/jamadermatol.2016.1336. PMID 27223861.
  20. ^ Shiran MS, Tan GC, Sabariah AR, Rampal L, Phang KS (mart 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.
  21. ^ Herawi M, Epstein JI (juni 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. S2CID 9054387.
  22. ^ Zhang H, Liu J, Cagle PT, Allen TC, Laga AC, Zander DS (januar 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.
  23. ^ Fomenkov A, Huang YP, Topaloglu O, Brechman A, Osada M, Fomenkova T, et al. (juni 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.
  24. ^ Yi R, Poy MN, Stoffel M, Fuchs E (mart 2008). "A skin microRNA promotes differentiation by repressing 'stemness'". Nature. 452 (7184): 225–9. doi:10.1038/nature06642. PMC 4346711. PMID 18311128.
  25. ^ Aberdam D, Candi E, Knight RA, Melino G (decembar 2008). "miRNAs, 'stemness' and skin". Trends in Biochemical Sciences. 33 (12): 583–91. doi:10.1016/j.tibs.2008.09.002. PMID 18848452. Arhivirano s originala, 21. 4. 2013.
  26. ^ Prieto-Garcia, C.; Hartmann, O; Reissland, M.; Braun, F.; Fischer, T.; Walz, S.; Fischer, A.; Calzado, M.; Orian, A.; Rosenfeldt, M.; Eilers, M.; E.Diefenbacher, M. (Jun 2019). "The USP28-∆Np63 axis is a vulnerability of squamous tumours". bioRxiv (jezik: engleski): 683508. doi:10.1101/683508. S2CID 198263967.
  27. ^ Prieto-Garcia C, Hartmann O, Reissland M, Braun F, Fischer T, Walz S, et al. (mart 2020). "Maintaining protein stability of ∆Np63 via USP28 is required by squamous cancer cells". EMBO Molecular Medicine. 12 (4): e11101. doi:10.15252/emmm.201911101. PMC 7136964. PMID 32128997.

Dopunska literatura

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Vanjski linkovi

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TP63 detalji ljudskog genoma u UCSC Genome Browser.