WT1

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Wilms tumor protein 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

WT1
Identifiers
SymbolWT1
PfamPF02165
InterProIPR000976

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

Wilm's tumour tumor suppressor gene1 (WT1) causes an embryonic malignancy of the kidney, affecting around 1 in 10,000 infants. It occurs in both sporadic and hereditary forms. Inactivation of WT1 causes Wilm's 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.[3][7][8][9]

WT1 is mutated in a mutually exclusive manner with TET2, IDH1, and IDH2 in acute myeloid leukemia.[10] 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,[11] representing an important feature of a new regulatory WIT pathway linked to the development of AML.[12]

The serine protease HtrA2 binds to WT1 and it cleaves WT1 at multiple sites following the treatment with cytotoxic drugs.[13][14]

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.[15]

As a drug target

WT1 has been ranked by the National Cancer Institute (NCI) as the Number 1 target for cancer immunotherapy.[16][17]

A vaccine that induces an innate immune response against WT1 is in clinical trials for various cancers.[16][17][18]

Interactions

WT1 has been shown to interact with TET2,[11] U2AF2,[19] PAWR,[20] UBE2I[21] and WTAP.[22] In combination with Cited2 activates WT1 the Steroidogenic factor 1[23]

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.[24][25]

Editing is tissue specific and developmentally regulated. Editing shown to be restricted in testis and kidney in the rat.[24] Editing of this gene product has been found to occur in mice and rats as well as humans.[24][26]

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)[24]

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, rat and humans have conserved sequences flanking the editing site consisting of 10 nucleotides before the editing site and four after the site.[24]

Effects of editing

RNA editing results in an alternative amino acid being translated.[24] The changes in amino acid occur in a region identified as a domain involved in transcription activation function.[27]

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.[26]

References

  1. ↑ Burgin AB, Parodos K, Lane DJ, Pace NR (Feb 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.
  2. ↑ Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (Feb 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.
  3. ↑ 3.0 3.1 Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA (Feb 1990). "Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping". Nature. 343 (6260): 774–8. doi:10.1038/343774a0. PMID 2154702.
  4. ↑ Huang A, Campbell CE, Bonetta L, McAndrews-Hill MS, Chilton-MacNeill S, Coppes MJ, Law DJ, Feinberg AP, Yeger H, Williams BR (Nov 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.
  5. ↑ "Entrez Gene: WT1 Wilms tumor 1".
  6. ↑ 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.
  7. ↑ Rauscher FJ (Jul 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. PMID 8393820.
  8. ↑ Buckler AJ, Pelletier J, Haber DA, Glaser T, Housman DE (Mar 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.
  9. ↑ Little MH, Prosser J, Condie A, Smith PJ, Van Heyningen V, Hastie ND (Jun 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.
  10. ↑ 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 (Dec 2014). "DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia". Cell Reports. 9 (5): 1841–55. doi:10.1016/j.celrep.2014.11.004. PMC 4267494. PMID 25482556.
  11. ↑ 11.0 11.1 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 (Feb 2015). "WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation". Molecular Cell. 57 (4): 662–73. doi:10.1016/j.molcel.2014.12.023. PMC 4336627. PMID 25601757.
  12. ↑ Sardina JL, Graf T (Feb 2015). "A new path to leukemia with WIT". Molecular Cell. 57 (4): 573–4. doi:10.1016/j.molcel.2015.02.005. PMID 25699704.
  13. ↑ Essafi A, Hastie ND (Jan 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.
  14. ↑ Hartkamp J, Carpenter B, Roberts SG (Jan 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.
  15. ↑ Leong AS, Cooper K, Leong FJ (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. pp. 447–448. ISBN 1-84110-100-1.
  16. ↑ 16.0 16.1 SELLAS Life Sciences Announces Positive WT1 Cancer Vaccine (galinpepimut-S) Clinical Results at the 13th International Conference of the International Mesothelioma Interest Group (iMig)
  17. ↑ 17.0 17.1 Pleural mesothelioma WT1 vaccine is renamed "galinpepimut-S"
  18. ↑ 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". Curr Med Chem. 13: 2345–52. PMID 16918359.
  19. ↑ Davies RC, Calvio C, Bratt E, Larsson SH, Lamond AI, Hastie ND (Oct 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.
  20. ↑ Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, Rangnekar VM, Shi Y (Dec 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.
  21. ↑ Wang ZY, Qiu QQ, Seufert W, Taguchi T, Testa JR, Whitmore SA, Callen DF, Welsh D, Shenk T, Deuel TF (Oct 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.
  22. ↑ Little NA, Hastie ND, Davies RC (Sep 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.
  23. ↑ Val P, Martinez-Barbera J-P, Swain A (Jun 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.
  24. ↑ 24.0 24.1 24.2 24.3 24.4 24.5 Sharma PM, Bowman M, Madden SL, Rauscher FJ, Sukumar S (Mar 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.
  25. ↑ Wagner KD, Wagner N, Schedl A (May 2003). "The complex life of WT1". Journal of Cell Science. 116 (Pt 9): 1653–8. doi:10.1242/jcs.00405. PMID 12665546.
  26. ↑ 26.0 26.1 Mrowka C, Schedl A (Nov 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.
  27. ↑ Wang ZY, Qiu QQ, Deuel TF (May 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.

Further reading

  • Haber DA, Buckler AJ (Feb 1992). "WT1: a novel tumor suppressor gene inactivated in Wilms' tumor". The New Biologist. 4 (2): 97–106. PMID 1313285.
  • Rauscher FJ (Jul 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. PMID 8393820.
  • Lee SB, Haber DA (Mar 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 (Aug 2001). "WT1 proteins: functions in growth and differentiation". Gene. 273 (2): 141–61. doi:10.1016/S0378-1119(01)00593-5. PMID 11595161.
  • Lim HN, Hughes IA, Hawkins JR (Dec 2001). "Clinical and molecular evidence for the role of androgens and WT1 in testis descent". Molecular and Cellular Endocrinology. 185 (1–2): 43–50. doi:10.1016/S0303-7207(01)00631-1. PMID 11738793.
  • Heathcott RW, Morison IM, Gubler MC, Corbett R, Reeve AE (Apr 2002). "A review of the phenotypic variation due to the Denys-Drash syndrome-associated germline WT1 mutation R362X". Human Mutation. 19 (4): 462. doi:10.1002/humu.9031. PMID 11933209.
  • Wagner KD, Wagner N, Schedl A (May 2003). "The complex life of WT1". Journal of Cell Science. 116 (Pt 9): 1653–8. doi:10.1242/jcs.00405. PMID 12665546.
  • Amini Nik S, Hohenstein P, Jadidizadeh A, Van Dam K, Bastidas A, Berry RL, Patek CE, Van der Schueren B, Cassiman JJ, Tejpar S (Mar 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.
  • Niaudet P, Gubler MC (Nov 2006). "WT1 and glomerular diseases". Pediatric Nephrology. 21 (11): 1653–60. doi:10.1007/s00467-006-0208-1. PMID 16927106.
  • Coosemans A, Nik SA, Caluwaerts S, Lambin S, Verbist G, Van Bree R, Schelfhout V, de Jonge E, Dalle I, Jacomen G, Cassiman JJ, Moerman P, Vergote I, Amant F (Jul 2007). "Upregulation of Wilms' tumour gene 1 (WT1) in uterine sarcomas". European Journal of Cancer. 43 (10): 1630–7. doi:10.1016/j.ejca.2007.04.008. PMID 17531467.
  • Hohenstein P, Hastie ND (Oct 2006). "The many facets of the Wilms' tumour gene, WT1". Human Molecular Genetics. 15 Spec No 2: R196–201. doi:10.1093/hmg/ddl196. PMID 16987884.

External links

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