TP63
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]
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
urediDužina polipeptidnog lanca je 680 aminokiselina, a molekulska težina Da. 76 785[11]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MNFETSRCAT | LQYCPDPYIQ | RFVETPAHFS | WKESYYRSTM | SQSTQTNEFL | ||||
SPEVFQHIWD | FLEQPICSVQ | PIDLNFVDEP | SEDGATNKIE | ISMDCIRMQD | ||||
SDLSDPMWPQ | YTNLGLLNSM | DQQIQNGSSS | TSPYNTDHAQ | NSVTAPSPYA | ||||
QPSSTFDALS | PSPAIPSNTD | YPGPHSFDVS | FQQSSTAKSA | TWTYSTELKK | ||||
LYCQIAKTCP | IQIKVMTPPP | QGAVIRAMPV | YKKAEHVTEV | VKRCPNHELS | ||||
REFNEGQIAP | PSHLIRVEGN | SHAQYVEDPI | TGRQSVLVPY | EPPQVGTEFT | ||||
TVLYNFMCNS | SCVGGMNRRP | ILIIVTLETR | DGQVLGRRCF | EARICACPGR | ||||
DRKADEDSIR | KQQVSDSTKN | GDGTKRPFRQ | NTHGIQMTSI | KKRRSPDDEL | ||||
LYLPVRGRET | YEMLLKIKES | LELMQYLPQH | TIETYRQQQQ | QQHQHLLQKQ | ||||
TSIQSPSSYG | NSSPPLNKMN | SMNKLPSVSQ | LINPQQRNAL | TPTTIPDGMG | ||||
ANIPMMGTHM | PMAGDMNGLS | PTQALPPPLS | MPSTSHCTPP | PPYPTDCSIV | ||||
SFLARLGCSS | CLDYFTTQGL | TTIYQIEHYS | MDDLASLKIP | EQFRHAIWKG | ||||
ILDHRQLHEF | SSPSHLLRTP | SSASTVSVGS | SETRGERVID | AVRFTLRQTI | ||||
SFPPRDEWND | FNFDMDARRN | KQQRIKEEGE |
Funkcija
urediTumorski 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
urediMutacije 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.
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
urediUočeno 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
urediImunobojenje 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
urediPokazalo se da je TP63 u interakciji sa HNRPAB.[23] Također aktivira transkripciju IRF6 preko elementa pojačivača IRF6.[17]
Regulacija
urediPostoje 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
urediReference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000073282 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000022510 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ "UniProt, Q9H3D4" (jezik: engleski). Pristupljeno 1. 11. 2021.
- ^ 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, 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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
uredi- Little NA, Jochemsen AG (januar 2002). "p63". The International Journal of Biochemistry & Cell Biology. 34 (1): 6–9. doi:10.1016/S1357-2725(01)00086-3. PMID 11733180.
- van Bokhoven H, McKeon F (mart 2002). "Mutations in the p53 homolog p63: allele-specific developmental syndromes in humans". Trends in Molecular Medicine. 8 (3): 133–9. doi:10.1016/S1471-4914(01)02260-2. PMID 11879774.
- van Bokhoven H, Brunner HG (juli 2002). "Splitting p63". American Journal of Human Genetics. 71 (1): 1–13. doi:10.1086/341450. PMC 384966. PMID 12037717.
- Brunner HG, Hamel BC, van Bokhoven H (oktobar 2002). "P63 gene mutations and human developmental syndromes". American Journal of Medical Genetics. 112 (3): 284–90. doi:10.1002/ajmg.10778. PMID 12357472.
- Jacobs WB, Walsh GS, Miller FD (oktobar 2004). "Neuronal survival and p73/p63/p53: a family affair". The Neuroscientist. 10 (5): 443–55. doi:10.1177/1073858404263456. PMID 15359011. S2CID 39702742.
- Zusman I (2005). "The soluble p51 protein in cancer diagnosis, prevention and therapy". In Vivo. 19 (3): 591–8. PMID 15875781.
- Morasso MI, Radoja N (septembar 2005). "Dlx genes, p63, and ectodermal dysplasias". Birth Defects Research. Part C, Embryo Today. 75 (3): 163–71. doi:10.1002/bdrc.20047. PMC 1317295. PMID 16187309.
- Barbieri CE, Pietenpol JA (april 2006). "p63 and epithelial biology". Experimental Cell Research. 312 (6): 695–706. doi:10.1016/j.yexcr.2005.11.028. PMID 16406339.
- Shalom-Feuerstein R, Lena AM, Zhou H, De La Forest Divonne S, Van Bokhoven H, Candi E, et al. (maj 2011). "ΔNp63 is an ectodermal gatekeeper of epidermal morphogenesis". Cell Death and Differentiation. 18 (5): 887–96. doi:10.1038/cdd.2010.159. PMC 3131930. PMID 21127502.
Vanjski linkovi
uredi- TP73L protein, human na 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 lokacija ljudskog genoma UCSC Genome Browser.
TP63 detalji ljudskog genoma u UCSC Genome Browser.