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Wt1

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Wt1

WT1
Identifiers
Symbol WT1
Pfam PF02165
InterPro IPR000976
Wilms tumor 1

PDB rendering based on 1xf7.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; AWT1; EWS-WT1; GUD; NPHS4; WAGR; WIT-2; WT33
External IDs GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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

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 is 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]

The serine protease HtrA2 binds to WT1 and it cleaves WT1 at multiple sites following the treatment with cytotoxic drugs.[10][11]

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.[12]

Interactions

WT1 has been shown to interact with U2AF2,[13] PAWR,[14] UBE2I[15] and WTAP.[16]

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.[17][18]

Editing is tissue specific and developmentally regulated. Editing shown to be restricted in testis and kidney in the rat.[17] Editing of this gene product has been found to occur in mice and rats as well as humans.[17][19]

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)[17]

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.[17]

Effects of editing

RNA editing results in an alternative amino acid being translated.[17] The changes in amino acid occur in a region identified as a domain involved in transcription activation function.[20]

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.[19]

References

  1. ^ Burgin AB, Parodos K, Lane DJ, Pace NR (February 1990). "The excision of intervening sequences from Salmonella 23S ribosomal RNA". Cell 60 (3): 405–14.  
  2. ^ Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (February 1990). "Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus". Cell 60 (3): 509–20.  
  3. ^ a b Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA (February 1990). "Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping". Nature 343 (6260): 774–8.  
  4. ^ Huang A, Campbell CE, Bonetta L, McAndrews-Hill MS, Chilton-MacNeill S, Coppes MJ, Law DJ, Feinberg AP, Yeger H, Williams BR (November 1990). "Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor". Science 250 (4983): 991–4.  
  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 Res 9 (4): R43.  
  7. ^ Rauscher FJ (July 1993). "The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor". FASEB J. 7 (10): 896–903.  
  8. ^ Buckler AJ, Pelletier J, Haber DA, Glaser T, Housman DE (March 1991). "Isolation, characterization, and expression of the murine Wilms' tumor gene (WT1) during kidney development". Mol. Cell. Biol. 11 (3): 1707–12.  
  9. ^ Little MH, Prosser J, Condie A, Smith PJ, Van Heyningen V, Hastie ND (June 1992). "Zinc finger point mutations within the WT1 gene in Wilms tumor patients". Proc. Natl. Acad. Sci. U.S.A. 89 (11): 4791–5.  
  10. ^ Essafi A, Hastie ND (January 2010). "WT1 the oncogene: a tale of death and HtrA". Mol. Cell 37 (2): 153–5.  
  11. ^ Hartkamp J, Carpenter B, Roberts SG (January 2010). "The Wilms' tumor suppressor protein WT1 is processed by the serine protease HtrA2/Omi". Mol. Cell 37 (2): 159–71.  
  12. ^ Leong AS-Y, Cooper K, Leong FJW-M (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. pp. 447–448.  
  13. ^ Davies RC, Calvio C, Bratt E, Larsson SH, Lamond AI, Hastie ND (October 1998). "WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes". Genes Dev. 12 (20): 3217–25.  
  14. ^ Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, Rangnekar VM, Shi Y (December 1996). "A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1". Mol. Cell. Biol. 16 (12): 6945–56.  
  15. ^ Wang ZY, Qiu QQ, Seufert W, Taguchi T, Testa JR, Whitmore SA, Callen DF, Welsh D, Shenk T, Deuel TF (October 1996). "Molecular cloning of the cDNA and chromosome localization of the gene for human ubiquitin-conjugating enzyme 9". J. Biol. Chem. 271 (40): 24811–6.  
  16. ^ Little NA, Hastie ND, Davies RC (September 2000). "Identification of WTAP, a novel Wilms' tumour 1-associating protein". Hum. Mol. Genet. 9 (15): 2231–9.  
  17. ^ a b c d e f Sharma PM, Bowman M, Madden SL, Rauscher FJ, Sukumar S (March 1994). "RNA editing in the Wilms' tumor susceptibility gene, WT1".  
  18. ^ Wagner KD, Wagner N, Schedl A (May 2003). "The complex life of WT1".  
  19. ^ a b Mrowka C, Schedl A (November 2000). "Wilms' tumor suppressor gene WT1: from structure to renal pathophysiologic features".  
  20. ^ Wang ZY, Qiu QQ, Deuel TF (May 1993). "The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains".  

Further reading

External links

  • GeneReviews/NCBI/NIH/UW entry on Aniridia
  • OMIM entries on Aniridia
  • GeneReviews/NIH/NCBI/UW entry on Wilms Tumor Overview
  • http://darned.ucc.ie
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