Wilms tumor protein explained

Wilms tumor protein (WT33) is a protein that in humans is encoded by the WT1 gene on chromosome 11p.[1] [2] [3] [4]

Function

This gene encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline / glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system, and it is mutated in a subset of patients with Wilms' tumor, the gene's namesake. Multiple transcript variants, resulting from alternative splicing at two coding exons, have been well characterized. There is also evidence for the use of non-AUG (CUG) translation initiation site upstream of, and in-frame with the first AUG, leading to additional isoforms.[5]

Structure

Symbol:WT1
WT1
Pfam:PF02165
Interpro:IPR000976
Align:left

The WT1 gene product shows similarity to the zinc fingers of the mammalian growth regulated early growth response protein 1 (EGR1) and (EGR2) proteins.[6]

Clinical significance

Mutations of Wilms' tumor suppressor gene1 (WT1) are associated with embryonic malignancy of the kidney, affecting around 1-9 in 100,000 infants.[7] It occurs in both sporadic and hereditary forms. Inactivation of WT1 causes Wilms tumour, and Denys-Drash syndrome (DDS), leading to nephropathy and genital abnormalities. The WT1 protein has been found to bind a host of cellular factors, e.g. p53, a known tumor suppressor.[8] [9] [10] Despite the name, WT1 mutation is found in only about 5-10% of Wilms Tumor cases.[11] Some other genes associated with this disease are BRCA2 and GPC3.

WT1 is mutated in a mutually exclusive manner with TET2, IDH1, and IDH2 in acute myeloid leukemia.[12] TET2 can be recruited by WT1 to its target genes and activates WT1-target genes by converting 5mC into 5hmC residues at the genes’ promoters,[13] representing an important feature of a new regulatory WIT pathway linked to the development of AML.[14]

The serine protease HtrA2 binds to WT1 and it cleaves WT1 at multiple sites following the treatment with cytotoxic drugs.[15] [16]

Using immunohistochemistry, WT1 protein can be demonstrated in the cell nuclei of 75% of mesotheliomas and in 93% of ovarian serous carcinomas, as well as in benign mesothelium and fallopian tube epithelium. This allows these tumours to be distinguished from other, similar, cancers, such as adenocarcinoma. Antibodies to the WT1 protein, however, also frequently cross-react with cytoplasmic proteins in a variety of benign and malignant cells, so that only nuclear staining can be considered diagnostic.[17]

Mutation in WT1 causes predisposition to hernias.[18]

As a drug target

A vaccine that induces an acquired immune response against WT1 is in clinical trials for various cancers.[19] [20] [21] T cell therapies (TCR-T) are also being tested in clinical trials for leukemia.[22] [23]

Disease monitoring

WT1 gene is overexpressed in case of hematological malignancies. This fact is widely used for disease monitoring - evaluations of treatment success, as well as relapse or remission post-treatment checks. Preferably quantitative polymerase chain reaction (qPCR) is used to establish the levels of WT1 expression. The rising level of WT1 expression is significantly connected with disease progression and relapse of the proliferative disorder.[24] WT1 as a marker is used as a "golden standard" for monitoring of acute myeloid leukemia, however other hematological malignancies such as chronic myeloid leukemia or myeloproliferative syndrome can manifest with overexpressed WT1 and for in specific cases WT1 monitoring can be used even in patients diagnosed with those types of cancer.[25]

Interactions

WT1 has been shown to interact with TET2,[13] U2AF2,[26] PAWR,[27] UBE2I[28] and WTAP.[29] In combination with Cited2 activates WT1 the Steroidogenic factor 1[30]

RNA editing

There is some evidence for RNA editing of human WT1 mRNA. As with alternative splicing of the gene RNA editing increases the number of isoforms of this protein.[31] [32]

Editing is tissue specific and developmentally regulated. Editing shown to be restricted in testis and kidney in the rat.[31] Editing of this gene product has been found to occur in mice and rats as well as humans.[31] [33]

Editing type

The editing site is found at nucleotide position 839 found in exon 6 of the gene. It causes a codon change from a Proline codon (CCC) to a Leucine codon (CUC)[31]

The type of editing is a uridine to cytidine (U to C) base change. The editing reaction is thought to be an amidation of uridine which converts it to a cytidine. The relevance of this editing is unknown as is the enzyme responsible for this editing. The region where editing occurs like that of other editing sites, e.g., ApoB mRNA editing is conserved. Mice, rats and humans have conserved sequences flanking the editing site consisting of 10 nucleotides before the editing site and four after the site.[31]

Effects of editing

RNA editing results in an alternative amino acid being translated.[31] The changes in amino acid occur in a region identified as a domain involved in transcription activation function.[34]

Editing has been shown to decrease repressive regulation of transcription of growth promoting genes in vitro compared to the non edited protein. Although the physiological role of editing has yet to be determined, suggestions have been made that editing may play a role in the pathogenesis of Wilms tumour.[33]

Experimental models

WT1 gene can be found as well in the genome of mice. The mouse model with a WT1 knock-out shows symptoms corresponding to human pathophysiology. The mice were observed to have defects of urogenital tract similar to cases patients when WT1 signalling has been malfunctioning. The mouse had absent kidneys as their development failed during embryonic stages. This suggests that WT1 is unconditionally required for a proper kidney formation and development.[35]

Apart from that, the WT1 knock-out mice lacked several types of glands, such as gonads or adrenal glands. The effect of the knock-out was as well visible on heart and blood circulation - several abnormalities concerning heart and diaphragm, as well as troubles with swelling and lymph circulation were described. Due to those defects, the mouse died before it was even born.

Mouse model is used to study some specific disorder connected with WT1 expression, too, such as acute myeloid leukemia.[36] To examine the expression levels and localisation of WT1, a mouse model using WT1-GFP (green fluorescent protein) knock-in has been made. This model showed, that WT1 is significantly overexpressed in leukemic cells compared to none or minor expression in normal untransformed cells from bone marrow, either hematopoietic stem cells or hematopoietic progenitors and precursors.[37]

Further reading

External links

Notes and References

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  2. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH . Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus . Cell . 60 . 3 . 509–20 . February 1990 . 2154335 . 10.1016/0092-8674(90)90601-A . 29092372 .
  3. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA . Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping . Nature . 343 . 6260 . 774–8 . February 1990 . 2154702 . 10.1038/343774a0 . 1990Natur.343..774G . 4235306 .
  4. Huang A, Campbell CE, Bonetta L, McAndrews-Hill MS, Chilton-MacNeill S, Coppes MJ, Law DJ, Feinberg AP, Yeger H, Williams BR . Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor . Science . 250 . 4983 . 991–4 . November 1990 . 2173145 . 10.1126/science.2173145 . 1990Sci...250..991H .
  5. Web site: Entrez Gene: WT1 Wilms tumor 1.
  6. Han Y, San-Marina S, Yang L, Khoury H, Minden MD . 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 . 2007 . 17634147 . 2206716 . 10.1186/bcr1743 . free .
  7. Web site: Orphanet: Nephroblastoma . www.orpha.net. 2019-05-06.
  8. Rauscher FJ . 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 . July 1993 . 8393820 . 10.1096/fasebj.7.10.8393820. free . 221754031 .
  9. Buckler AJ, Pelletier J, Haber DA, Glaser T, Housman DE . Isolation, characterization, and expression of the murine Wilms' tumor gene (WT1) during kidney development . Molecular and Cellular Biology . 11 . 3 . 1707–12 . March 1991 . 1671709 . 369476 . 10.1128/mcb.11.3.1707 .
  10. Little MH, Prosser J, Condie A, Smith PJ, Van Heyningen V, Hastie ND . 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 . June 1992 . 1317572 . 49173 . 10.1073/pnas.89.11.4791 . 1992PNAS...89.4791L . free .
  11. Davidoff AM . Wilms tumor . Advances in Pediatrics . 59 . 1 . 247–267 . 2012 . 22789581 . 3589819 . 10.1016/j.yapd.2012.04.001 .
  12. 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 . DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia . Cell Reports . 9 . 5 . 1841–1855 . December 2014 . 25482556 . 4267494 . 10.1016/j.celrep.2014.11.004 .
  13. 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 . WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation . Molecular Cell . 57 . 4 . 662–673 . February 2015 . 25601757 . 4336627 . 10.1016/j.molcel.2014.12.023 .
  14. Sardina JL, Graf T . A new path to leukemia with WIT . Molecular Cell . 57 . 4 . 573–574 . February 2015 . 25699704 . 10.1016/j.molcel.2015.02.005 . free .
  15. Essafi A, Hastie ND . WT1 the oncogene: a tale of death and HtrA . Molecular Cell . 37 . 2 . 153–5 . January 2010 . 20122396 . 10.1016/j.molcel.2010.01.010 . free .
  16. Hartkamp J, Carpenter B, Roberts SG . The Wilms' tumor suppressor protein WT1 is processed by the serine protease HtrA2/Omi . Molecular Cell . 37 . 2 . 159–71 . January 2010 . 20122399 . 2815029 . 10.1016/j.molcel.2009.12.023 .
  17. Book: Leong AS, Cooper K, Leong FJ . 2003 . Manual of Diagnostic Cytology . 2 . Greenwich Medical Media, Ltd. . 447–448 . 978-1-84110-100-2 .
  18. Jorgenson E, Makki N, Shen L, Chen DC, Tian C, Eckalbar WL, Hinds D, Ahituv N, Avins A . A genome-wide association study identifies four novel susceptibility loci underlying inguinal hernia . Nature Communications . 6 . 10130 . December 2015 . 26686553 . 4703831 . 10.1038/ncomms10130 .
  19. Web site: SELLAS Life Sciences Announces Positive WT1 Cancer Vaccine (galinpepimut-S) Clinical Results at the 13th International Conference of the International Mesothelioma Interest Group (iMig) . 2016-05-08 . 2016-06-04 . https://web.archive.org/web/20160604123918/http://sellaslifesciences.com/2016/05/sellas-life-sciences-announces-positive-wt1-cancer-vaccine-galinpepimut-s-clinical-results-at-the-13th-international-conference-of-the-international-mesothelioma-interest-group-imig/ . dead .
  20. http://www.mymeso.org/2016/04/08/pleural-mesothelioma-wt1-vaccine-is-renamed-galinpepimut-s/ Pleural mesothelioma WT1 vaccine is renamed "galinpepimut-S"
  21. Oka Y, Tsuboi A, Kawakami M, Elisseeva OA, Nakajima H, Udaka K, Kawase I, Oji Y, Sugiyama H . Development of WT1 peptide cancer vaccine against hematopoietic malignancies and solid cancers . Current Medicinal Chemistry . 13 . 20 . 2345–52 . 16918359 . 2006 . 10.2174/092986706777935104 .
  22. Chapuis AG, Egan DN, Bar M, Schmitt TM, McAfee MS, Paulson KG, Voillet V, Gottardo R, Ragnarsson GB, Bleakley M, Yeung CC, Muhlhauser P, Nguyen HN, Kropp LA, Castelli L, Wagener F, Hunter D, Lindberg M, Cohen K, Seese A, McElrath MJ, Duerkopp N, Gooley TA, Greenberg PD . 6 . T cell receptor gene therapy targeting WT1 prevents acute myeloid leukemia relapse post-transplant . Nature Medicine . 25 . 7 . 1064–1072 . July 2019 . 31235963 . 6982533 . 10.1038/s41591-019-0472-9 . free .
  23. Tawara I, Kageyama S, Miyahara Y, Fujiwara H, Nishida T, Akatsuka Y, Ikeda H, Tanimoto K, Terakura S, Murata M, Inaguma Y, Masuya M, Inoue N, Kidokoro T, Okamoto S, Tomura D, Chono H, Nukaya I, Mineno J, Naoe T, Emi N, Yasukawa M, Katayama N, Shiku H . 6 . Safety and persistence of WT1-specific T-cell receptor gene-transduced lymphocytes in patients with AML and MDS . Blood . 130 . 18 . 1985–1994 . November 2017 . 28860210 . 10.1182/blood-2017-06-791202 . free .
  24. Candoni A, Toffoletti E, Gallina R, Simeone E, Chiozzotto M, Volpetti S, Fanin R . 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 . March 2011 . 20412098 . 10.1111/j.1399-0012.2010.01251.x . 6677442 . free .
  25. Sugiyama H . WT1 (Wilms' tumor gene 1): biology and cancer immunotherapy . Japanese Journal of Clinical Oncology . 40 . 5 . 377–87 . May 2010 . 20395243 . 10.1093/jjco/hyp194 . free .
  26. Davies RC, Calvio C, Bratt E, Larsson SH, Lamond AI, Hastie ND . WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes . Genes & Development . 12 . 20 . 3217–25 . October 1998 . 9784496 . 317218 . 10.1101/gad.12.20.3217 .
  27. Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, Rangnekar VM, Shi Y . 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 . December 1996 . 8943350 . 231698 . 10.1128/mcb.16.12.6945 .
  28. Wang ZY, Qiu QQ, Seufert W, Taguchi T, Testa JR, Whitmore SA, Callen DF, Welsh D, Shenk T, Deuel TF . 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 . October 1996 . 8798754 . 10.1074/jbc.271.40.24811 . free .
  29. Little NA, Hastie ND, Davies RC . Identification of WTAP, a novel Wilms' tumour 1-associating protein . Human Molecular Genetics . 9 . 15 . 2231–9 . September 2000 . 11001926 . 10.1093/oxfordjournals.hmg.a018914 . free .
  30. Val P, Martinez-Barbera JP, Swain A . Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage . Development . 134 . 12 . 2349–58 . June 2007 . 17537799 . 10.1242/dev.004390 . free .
  31. Sharma PM, Bowman M, Madden SL, Rauscher FJ, Sukumar S . RNA editing in the Wilms' tumor susceptibility gene, WT1 . Genes & Development . 8 . 6 . 720–31 . March 1994 . 7926762 . 10.1101/gad.8.6.720 . free .
  32. Wagner KD, Wagner N, Schedl A . The complex life of WT1 . Journal of Cell Science . 116 . Pt 9 . 1653–8 . May 2003 . 12665546 . 10.1242/jcs.00405 . free .
  33. Mrowka C, Schedl A . Wilms' tumor suppressor gene WT1: from structure to renal pathophysiologic features . Journal of the American Society of Nephrology . 11 . S106–15 . November 2000 . Suppl 16 . 10.1681/ASN.V11suppl_2s106 . 11065340 . free .
  34. Wang ZY, Qiu QQ, Deuel TF . The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains . The Journal of Biological Chemistry . 268 . 13 . 9172–5 . May 1993 . 10.1016/S0021-9258(18)98329-8 . 8486616 . free .
  35. Ozdemir DD, Hohenstein P . Wt1 in the kidney--a tale in mouse models . Pediatric Nephrology . 29 . 4 . 687–93 . April 2014 . 24240471 . 10.1007/s00467-013-2673-7 . 2019375 .
  36. Gaiger A, Reese V, Disis ML, Cheever MA . Immunity to WT1 in the animal model and in patients with acute myeloid leukemia . Blood . 96 . 4 . 1480–9 . August 2000 . 10942395 . 10.1182/blood.V96.4.1480. free .
  37. Hosen N, Shirakata T, Nishida S, Yanagihara M, Tsuboi A, Kawakami M, Oji Y, Oka Y, Okabe M, Tan B, Sugiyama H, Weissman IL . The Wilms' tumor gene WT1-GFP knock-in mouse reveals the dynamic regulation of WT1 expression in normal and leukemic hematopoiesis . Leukemia . 21 . 8 . 1783–91 . August 2007 . 17525726 . 10.1038/sj.leu.2404752 . free .

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