WT1

S Wikipedije, slobodne enciklopedije
WT1
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1XF7, 2JP9, 2JPA, 2PRT, 3HPJ, 3MYJ, 4R2E, 4R2P, 4R2Q, 4R2R, 4R2S, 4WUU

Identifikatori
AliasiWT1
Vanjski ID-jeviOMIM: 607102 MGI: 98968 HomoloGene: 11536 GeneCards: WT1
Lokacija gena (čovjek)
Hromosom 11 (čovjek)
Hrom.Hromosom 11 (čovjek)[1]
Hromosom 11 (čovjek)
Genomska lokacija za WT1
Genomska lokacija za WT1
Bend11p13Početak32,387,775 bp[1]
Kraj32,435,564 bp[1]
Lokacija gena (miš)
Hromosom 2 (miš)
Hrom.Hromosom 2 (miš)[2]
Hromosom 2 (miš)
Genomska lokacija za WT1
Genomska lokacija za WT1
Bend2 E3|2 55.06 cMPočetak104,956,874 bp[2]
Kraj105,003,961 bp[2]
Obrazac RNK ekspresije


Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• sequence-specific DNA binding
• vezivanje sa DNK
• GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity
• vezivanje iona cinka
• GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific
• C2H2 zinc finger domain binding
• vezivanje iona metala
• GO:0001948, GO:0016582 vezivanje za proteine
• vezivanje sa RNK
• nucleic acid binding
• double-stranded methylated DNA binding
• hemi-methylated DNA-binding
• GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific
Ćelijska komponenta• citoplazma
• nuclear speck
• nukleoplazma
• Jedarce
• jedro
• citosol
Biološki proces• germ cell development
• adrenal cortex formation
• ureteric bud development
• negative regulation of translation
• male gonad development
• male genitalia development
• GO:0009373 regulation of transcription, DNA-templated
• epithelial cell differentiation
• glomerular basement membrane development
• diaphragm development
• Nefrogeneza
• GO:0044324, GO:0003256, GO:1901213, GO:0046019, GO:0046020, GO:1900094, GO:0061216, GO:0060994, GO:1902064, GO:0003258, GO:0072212 regulation of transcription by RNA polymerase II
• posterior mesonephric tubule development
• visceral serous pericardium development
• metanephric epithelium development
• negative regulation of apoptotic process
• glomerulus development
• GO:1901227 negative regulation of transcription by RNA polymerase II
• adrenal gland development
• transcription, DNA-templated
• positive regulation of metanephric ureteric bud development
• Vaskulogeneza
• GO:0060469, GO:0009371 positive regulation of transcription, DNA-templated
• positive regulation of heart growth
• heart development
• negative regulation of female gonad development
• branching involved in ureteric bud morphogenesis
• regulation of animal organ formation
• Sistem određivanja spola
• negative regulation of cell growth
• Prerada RNK
• cardiac muscle cell fate commitment
• tissue development
• positive regulation of apoptotic process
• camera-type eye development
• metanephric S-shaped body morphogenesis
• thorax and anterior abdomen determination
• GO:0045996 negative regulation of transcription, DNA-templated
• gonad development
• metanephric mesenchyme development
• cellular response to gonadotropin stimulus
• positive regulation of male gonad development
• cellular response to cAMP
• negative regulation of cell population proliferation
• mesenchymal to epithelial transition
• negative regulation of metanephric glomerular mesangial cell proliferation
• GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II
• transcription by RNA polymerase II
• glomerular visceral epithelial cell differentiation
• GO:1901313 positive regulation of gene expression
• positive regulation of pri-miRNA transcription by RNA polymerase II
• positive regulation of DNA methylation
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

7490

22431

Ensembl

ENSG00000184937

ENSMUSG00000016458

UniProt

P19544

P22561
Q199A7

RefSeq (mRNK)
NM_024426
NM_000378
NM_001198551
NM_001198552
NM_024424

NM_024425
NM_001367854

NM_144783

RefSeq (bjelančevina)
NP_000369
NP_001185480
NP_001185481
NP_077742
NP_077744

NP_001354783
NP_000369.3
NP_001185480.1
NP_001185481.1
NP_077742.2
NP_077744.3

NP_659032

Lokacija (UCSC)Chr 11: 32.39 – 32.44 MbChr 2: 104.96 – 105 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Protein Wilmsovog tumora je protein koji je kod ljudi kodiran gen WT1 sa kratkog (p) kraka hromosoma 11.[5][6][7][8]

Aminokiselinska sekvenca[uredi | uredi izvor]

Dužina polipeptidnog lanca je 449 aminokiselina, a molekulska težina 49.188 Da.[9]

1020304050
MGSDVRDLNALLPAVPSLGGGGGCALPVSGAAQWAPVLDFAPPGASAYGS
LGGPAPPPAPPPPPPPPPHSFIKQEPSWGGAEPHEEQCLSAFTVHFSGQF
TGTAGACRYGPFGPPPPSQASSGQARMFPNAPYLPSCLESQPAIRNQGYS
TVTFDGTPSYGHTPSHHAAQFPNHSFKHEDPMGQQGSLGEQQYSVPPPVY
GCHTPTDSCTGSQALLLRTPYSSDNLYQMTSQLECMTWNQMNLGATLKGV
AAGSSSSVKWTEGQSNHSTGYESDNHTTPILCGAQYRIHTHGVFRGIQDV
RRVPGVAPTLVRSASETSEKRPFMCAYPGCNKRYFKLSHLQMHSRKHTGE
KPYQCDFKDCERRFSRSDQLKRHQRRHTGVKPFQCKTCQRKFSRSDHLKT
HTRTHTGKTSEKPFSCRWPSCQKKFARSDELVRHHNMHQRNMTKLQLAL

Struktura[uredi | uredi izvor]

Protein Wilmskovog tumora
Identifikatori
SimbolWT1

Proizvod gene WT1 pokazuje sličnost sa cinkovim prstima sisara rastom reguliranih proteina 1 za odgovor na rani rast (EGR1) i (EGR2) proteina.[10]

Funkcija[uredi | uredi izvor]

Ovaj 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]

Editiranje RNK[uredi | uredi izvor]

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[uredi | uredi izvor]

Mjesto 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[uredi | uredi izvor]

Editiranje 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[uredi | uredi izvor]

Mutacije 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[uredi | uredi izvor]

Gen 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[uredi | uredi izvor]

Pokazano 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[uredi | uredi izvor]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000184937 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000016458 - 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. ^ Burgin AB, Parodos K, Lane DJ, Pace NR (februar 1990). "The excision of intervening sequences from Salmonella 23S ribosomal RNA". Cell. 60 (3): 405–14. doi:10.1016/0092-8674(90)90592-3. PMID 2406020. S2CID 39909491.
  6. ^ Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (februar 1990). "Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus". Cell. 60 (3): 509–20. doi:10.1016/0092-8674(90)90601-A. PMID 2154335. S2CID 29092372.
  7. ^ a b Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA (februar 1990). "Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping" (PDF). Nature. 343 (6260): 774–8. doi:10.1038/343774a0. PMID 2154702. S2CID 4235306.
  8. ^ Huang A, Campbell CE, Bonetta L, McAndrews-Hill MS, Chilton-MacNeill S, Coppes MJ, Law DJ, Feinberg AP, Yeger H, Williams BR (novembar 1990). "Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor". Science. 250 (4983): 991–4. doi:10.1126/science.2173145. PMID 2173145.
  9. ^ "UniProt, P19544". Pristupljeno 22. 8. 2021.
  10. ^ Han Y, San-Marina S, Yang L, Khoury H, Minden MD (2007). "The zinc finger domain of Wilms' tumor 1 suppressor gene (WT1) behaves as a dominant negative, leading to abrogation of WT1 oncogenic potential in breast cancer cells". Breast Cancer Research. 9 (4): R43. doi:10.1186/bcr1743. PMC 2206716. PMID 17634147.
  11. ^ "Entrez Gene: WT1 Wilms tumor 1".
  12. ^ a b c d e Sharma PM, Bowman M, Madden SL, Rauscher FJ, Sukumar S (mart 1994). "RNA editing in the Wilms' tumor susceptibility gene, WT1". Genes & Development. 8 (6): 720–31. doi:10.1101/gad.8.6.720. PMID 7926762.
  13. ^ Wagner KD, Wagner N, Schedl A (maj 2003). "The complex life of WT1". Journal of Cell Science. 116 (Pt 9): 1653–8. doi:10.1242/jcs.00405. PMID 12665546.
  14. ^ a b Mrowka C, Schedl A (novembar 2000). "Wilms' tumor suppressor gene WT1: from structure to renal pathophysiologic features". Journal of the American Society of Nephrology. 11 Suppl 16: S106–15. PMID 11065340.
  15. ^ Wang ZY, Qiu QQ, Deuel TF (maj 1993). "The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains". The Journal of Biological Chemistry. 268 (13): 9172–5. PMID 8486616.[mrtav link]
  16. ^ RESERVED, INSERM US14-- ALL RIGHTS. "Orphanet: Nephroblastoma". www.orpha.net. Pristupljeno 6. 5. 2019.
  17. ^ 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.
  18. ^ Buckler AJ, Pelletier J, Haber DA, Glaser T, Housman DE (mart 1991). "Isolation, characterization, and expression of the murine Wilms' tumor gene (WT1) during kidney development". Molecular and Cellular Biology. 11 (3): 1707–12. doi:10.1128/mcb.11.3.1707. PMC 369476. PMID 1671709.
  19. ^ Little MH, Prosser J, Condie A, Smith PJ, Van Heyningen V, Hastie ND (juni 1992). "Zinc finger point mutations within the WT1 gene in Wilms tumor patients". Proceedings of the National Academy of Sciences of the United States of America. 89 (11): 4791–5. doi:10.1073/pnas.89.11.4791. PMC 49173. PMID 1317572.
  20. ^ Davidoff, Andrew M. (2012). "Wilms Tumor". Advances in Pediatrics. 59 (1): 247–267. doi:10.1016/j.yapd.2012.04.001. PMC 3589819. PMID 22789581. Pristupljeno 28. 1. 2019.
  21. ^ Rampal R, Alkalin A, Madzo J, Vasanthakumar A, Pronier E, Patel J, Li Y, Ahn J, Abdel-Wahab O, Shih A, Lu C, Ward PS, Tsai JJ, Hricik T, Tosello V, Tallman JE, Zhao X, Daniels D, Dai Q, Ciminio L, Aifantis I, He C, Fuks F, Tallman MS, Ferrando A, Nimer S, Paietta E, Thompson CB, Licht JD, Mason CE, Godley LA, Melnick A, Figueroa ME, Levine RL (decembar 2014). "DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia". Cell Reports. 9 (5): 1841–1855. doi:10.1016/j.celrep.2014.11.004. PMC 4267494. PMID 25482556.
  22. ^ a b Wang Y, Xiao M, Chen X, Chen L, Xu Y, Lv L, Wang P, Yang H, Ma S, Lin H, Jiao B, Ren R, Ye D, Guan KL, Xiong Y (februar 2015). "WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation". Molecular Cell. 57 (4): 662–673. doi:10.1016/j.molcel.2014.12.023. PMC 4336627. PMID 25601757.
  23. ^ Sardina JL, Graf T (februar 2015). "A new path to leukemia with WIT". Molecular Cell. 57 (4): 573–574. doi:10.1016/j.molcel.2015.02.005. PMID 25699704.
  24. ^ Essafi A, Hastie ND (januar 2010). "WT1 the oncogene: a tale of death and HtrA". Molecular Cell. 37 (2): 153–5. doi:10.1016/j.molcel.2010.01.010. PMID 20122396.
  25. ^ Hartkamp J, Carpenter B, Roberts SG (januar 2010). "The Wilms' tumor suppressor protein WT1 is processed by the serine protease HtrA2/Omi". Molecular Cell. 37 (2): 159–71. doi:10.1016/j.molcel.2009.12.023. PMC 2815029. PMID 20122399.
  26. ^ Leong AS, Cooper K, Leong FJ (2003). Manual of Diagnostic Cytology (2 izd.). Greenwich Medical Media, Ltd. str. 447–448. ISBN 978-1-84110-100-2.
  27. ^ Jorgenson, E.; Makki, N.; Shen, L.; Chen, D. C.; Tian, C.; Eckalbar, W. L.; Hinds, D.; Ahituv, N.; Avins, A. (2015). "A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia - PubMed". Nature Communications. 6: 10130. doi:10.1038/ncomms10130. PMC 4703831. PMID 26686553.
  28. ^ Candoni A, Toffoletti E, Gallina R, Simeone E, Chiozzotto M, Volpetti S, Fanin R (mart 2011). "Monitoring of minimal residual disease by quantitative WT1 gene expression following reduced intensity conditioning allogeneic stem cell transplantation in acute myeloid leukemia". Clinical Transplantation. 25 (2): 308–16. doi:10.1111/j.1399-0012.2010.01251.x. PMID 20412098. S2CID 6677442.
  29. ^ Sugiyama H (maj 2010). "WT1 (Wilms' tumor gene 1): biology and cancer immunotherapy". Japanese Journal of Clinical Oncology. 40 (5): 377–87. doi:10.1093/jjco/hyp194. PMID 20395243.
  30. ^ Davies RC, Calvio C, Bratt E, Larsson SH, Lamond AI, Hastie ND (oktobar 1998). "WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes". Genes & Development. 12 (20): 3217–25. doi:10.1101/gad.12.20.3217. PMC 317218. PMID 9784496.
  31. ^ Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, Rangnekar VM, Shi Y (decembar 1996). "A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1". Molecular and Cellular Biology. 16 (12): 6945–56. doi:10.1128/mcb.16.12.6945. PMC 231698. PMID 8943350.
  32. ^ Wang ZY, Qiu QQ, Seufert W, Taguchi T, Testa JR, Whitmore SA, Callen DF, Welsh D, Shenk T, Deuel TF (oktobar 1996). "Molecular cloning of the cDNA and chromosome localization of the gene for human ubiquitin-conjugating enzyme 9". The Journal of Biological Chemistry. 271 (40): 24811–6. doi:10.1074/jbc.271.40.24811. PMID 8798754.
  33. ^ Little NA, Hastie ND, Davies RC (septembar 2000). "Identification of WTAP, a novel Wilms' tumour 1-associating protein". Human Molecular Genetics. 9 (15): 2231–9. doi:10.1093/oxfordjournals.hmg.a018914. PMID 11001926.
  34. ^ Val P, Martinez-Barbera JP, Swain A (juni 2007). "Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage". Development. 134 (12): 2349–58. doi:10.1242/dev.004390. PMID 17537799.

Dopunska literatura[uredi | uredi izvor]

Vanjski linkovi[uredi | uredi izvor]

Šablon:Supresorski geni tumora

Preuzeto iz "https://bs.wikipedia.org/w/index.php?title=WT1&oldid=3506425"