WT1
Protein Wilmsovog tumora je protein koji je kod ljudi kodiran gen WT1 sa kratkog (p) kraka hromosoma 11.[5][6][7][8]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 449 aminokiselina, a molekulska težina 49.188 Da.[9]
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MGSDVRDLNA | LLPAVPSLGG | GGGCALPVSG | AAQWAPVLDF | APPGASAYGS | ||||
| LGGPAPPPAP | PPPPPPPPHS | FIKQEPSWGG | AEPHEEQCLS | AFTVHFSGQF | ||||
| TGTAGACRYG | PFGPPPPSQA | SSGQARMFPN | APYLPSCLES | QPAIRNQGYS | ||||
| TVTFDGTPSY | GHTPSHHAAQ | FPNHSFKHED | PMGQQGSLGE | QQYSVPPPVY | ||||
| GCHTPTDSCT | GSQALLLRTP | YSSDNLYQMT | SQLECMTWNQ | MNLGATLKGV | ||||
| AAGSSSSVKW | TEGQSNHSTG | YESDNHTTPI | LCGAQYRIHT | HGVFRGIQDV | ||||
| RRVPGVAPTL | VRSASETSEK | RPFMCAYPGC | NKRYFKLSHL | QMHSRKHTGE | ||||
| KPYQCDFKDC | ERRFSRSDQL | KRHQRRHTGV | KPFQCKTCQR | KFSRSDHLKT | ||||
| HTRTHTGKTS | EKPFSCRWPS | CQKKFARSDE | LVRHHNMHQR | NMTKLQLAL |
Struktura
uredi| Protein Wilmskovog tumora | |
|---|---|
 | |
| Identifikatori | |
| Simbol | WT1 |
Proizvod gene WT1 pokazuje sličnost sa cinkovim prstima sisara rastom reguliranih proteina 1 za odgovor na rani rast (EGR1) i (EGR2) proteina.[10]
Funkcija
urediOvaj gen kodira faktor transkripcije koji sadrži četiri motiva cinkovog prsta na C-kraju i prolin / glutamin-bogati domen koji veže DNK na N-terminalu. Ima bitnu ulogu u normalnom razvoju urogenitalnog sistema, a mutiran je u podskupini pacijenata sa Wilmsovim timorom, imenjakom gena. Više varijanti transkripta, koje su rezultat alternativne prerade na dva kodirajuća egzona, dobro su okarakterizirane. Postoje i dokazi o korištenju ne-AUG (CUG) mjesta inicijacije translacije uzvodno i unutar okvira s prvim AUG-om, što dovodi do dodatnih izoformi.[11]
Postoje neki dokazi za editiranje RNK iRNK ljudskogWT1. Kao i kod alternativne prerade ediriranje RNK gena povećava broj izoformi ovog proteina.[12][13]
Editiranje je specifično za tkivo i razvojno je regulirano. Pokazalo se da je kod pacova ograničeno u sjemenicima i bubrezima.[12] Utvrđeno je da se editiranje ovog genskog proizvoda kod miševa i pacova događa kao i kod ljudi.[12][14]
Tip editiranja
urediMjesto editiranja nalazi se na nukleotidnoj poziciji 839 koja se nalazi u genakom egzonu 6. To uzrokuje promjenu kodona iz prolinskog (CCC) u leucinski kodon (CUC) [12]
Tipovi editirnja su promjene baza uridin u citidin (U u C). Smatra se da je reakcija editiranja amidijacija uridina koja ga pretvara u citidin. Relevantnost ovog uređivanja nije poznata, kao što je enzim odgovoran za ovo editiranje. Područje u kojem se događa kao i na drugim editirajućim mjestima, npr. edititanje ApoB iRNK, je konzervirano. Miševi, pacovi i ljudi imaju konzervirane sekvence koje se nalaze uz bok mjesta editiranja, koje se sastoji od 10 nukleotida prije editiranja i četiri nakon mjesta.[12]
Efekti editiranja
urediEditiranje RNK rezultira translacijom alternativne aminokiseline. Promjene u aminokiselini događaju se u regiji identificiranoj kao domen uključen u funkciju aktivacije transkripcije.[15]
Pokazalo se da editiranje smanjuje represivnu regulaciju transkripcije gena za podsticanje rasta in vitro u usporedbi s needitiranim proteinom. Iako fiziološka uloga editiranja tek treba da se utvrdi, iznijete su sugestije da editiranje može imati ulogu u patogenezi Wilmsovog tumora.[14]
Klinički značaj
urediMutacije Wilmsovog gena sopresije tumora 1 (WT1) povezane su s embrionskim malignitetom bubrega, pogađajući oko 1-9 na 100.000 dojenčadi.[16] Javlja se u sporadičnim i nasljednim oblicima. Inaktiviranje uzroka WT1 Wilmsovog tumora i Denys-Drashov sindrom (DDS), što dovodi do nefropatije i genitalnih abnormalnosti. Utvrđeno je da protein WT1 veže čitav niz ćelijskih faktora, npr. p53, poznati supresor tumora.[7][17][18][19] Unatoč imenu, WT1 mutacija nalazi se u samo oko 5-10% slučajeva Wilmsovog tumor.[20] Neki drugi geni povezani s ovom bolešću su BRCA2 and GPC3
U akutnoj mijeloidnoj leukemiji, WT1 je mutiran na međusobno isključujući način sa TET2, IDH1 i IDH2.[21] WT1 može regrutirati TET2 u svoje ciljne gene i aktivira gene ciljane na WT1, pretvaranjem 5mC u 5hmC ostatke kod promotorskih gena,[22] što predstavlja važnu karakteristiku novog regulatornog puta WIT-a povezanog s razvojem BPPN-a.[23]
Nakon tretmana citotoksičnim lijekovima, serin-proteaza HtrA2 veže se za WT1 i cijepa WT1 na više mjesta.[24][25]
Koristeći imunohistohemijski tretman, protein WT1 može se dokazati u jedru ćelija 75% mezotelioma i u 93% seroznih karcinoma jajnika, kao i u dobroćudnom mezotelu i jajovodnom epitelu. To omogućava razlikovanje ovih tumora od drugih, sličnih, vrsta raka, poput adenokarcinoma. Antitijela na protein WT1, međutim, također često međusobno reagiraju s citoplazmatskim proteinima u različitim dobroćudnim i zloćudnim ćelijama, tako da se samo jedarno bojenje može smatrati dijagnostičkim.[26]
Mutacija u WT1 uzrokuje predispoziciju za hernije.[27]
Praćenje bolesti
urediGen WT1 je prekomjerno eksprimiran u slučaju krvnih malignosti. Ova se činjenica široko koristi za praćenje bolesti – procjene uspješnosti liječenja, kao i relaps ili remisiju nakon liječenja. Poželjno je da se kvantitativna lančana reakcija polimeraze (qPCR) koristi za utvrđivanje nivoa ekspresije WT1. Porast ekspresije WT1 značajno je povezan s progresijom bolesti i relapsima proliferativnog poremećaja.[28] WT1 kao marker koristi se kao "zlatni standard" za praćenje akutne mijeloidne leukemije, ali i drugih krvnih zloćudnih bolesti, kao što je hronična mijeloidna leukemija ili mijeloproliferativni sindrom koji se može manifestirati sa prekomjernim WT1, a u posebnim slučajevima nadziranje WT1 može se koristiti čak i kod pacijenata kojima je dijagnosticiran Taj tip kancera.[29]
Interakcije
urediPokazano je da WT1 ima interakcije sa TET2,[22] U2AF2,[30] PAWR,[31] UBE2I[32] i WTAP.[33] U kombinaciji sa drugopomenutim, WT1 aktivira steroidogeni faktor 1[34]
Reference
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Dopunska literatura
uredi- Haber DA, Buckler AJ (februar 1992). "WT1: a novel tumor suppressor gene inactivated in Wilms' tumor". The New Biologist. 4 (2): 97–106. PMID 1313285.
- Rauscher FJ (juli 1993). "The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor". FASEB Journal. 7 (10): 896–903. doi:10.1096/fasebj.7.10.8393820. PMID 8393820.
- Lee SB, Haber DA (mart 2001). "Wilms tumor and the WT1 gene". Experimental Cell Research. 264 (1): 74–99. doi:10.1006/excr.2000.5131. PMID 11237525.
- Scharnhorst V, van der Eb AJ, Jochemsen AG (august 2001). "WT1 proteins: functions in growth and differentiation". Gene. 273 (2): 141–61. doi:10.1016/S0378-1119(01)00593-5. PMID 11595161.
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- Amini Nik S, Hohenstein P, Jadidizadeh A, Van Dam K, Bastidas A, Berry RL, Patek CE, Van der Schueren B, Cassiman JJ, Tejpar S (mart 2005). "Upregulation of Wilms' tumor gene 1 (WT1) in desmoid tumors". International Journal of Cancer. 114 (2): 202–8. doi:10.1002/ijc.20717. PMID 15540161. S2CID 26931961.
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