Wilms tumor protein

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WT1
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WT1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000184937

ENSMUSG00000016458

UniProt

P19544

P22561
Q199A7

RefSeq (mRNA)

NM_144783

RefSeq (protein)

NP_659032

Location (UCSC)Chr 11: 32.39 – 32.44 MbChr 2: 104.96 – 105 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Wilms tumor protein (WT33) is a protein that in humans is encoded by the WT1 gene on chromosome 11p.[5][6][7][8]

Function

This gene encodes a

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.[9]

Structure

WT1
Identifiers
SymbolWT1
PfamPF02165
InterProIPR000976
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

The WT1 gene

mammalian growth regulated early growth response protein 1 (EGR1) and (EGR2) proteins.[10]

Clinical significance

Mutations of Wilms'

nephropathy and genital abnormalities. The WT1 protein has been found to bind a host of cellular factors, e.g. p53, a known tumor suppressor.[7][12][13][14] Despite the name, WT1 mutation is found in only about 5-10% of Wilms Tumor cases.[15] Some other genes associated with this disease are BRCA2 and GPC3

WT1 is mutated in a

TET2, IDH1, and IDH2 in acute myeloid leukemia.[16] 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,[17] representing an important feature of a new regulatory WIT pathway linked to the development of AML.[18]

The serine protease

HtrA2 binds to WT1 and it cleaves WT1 at multiple sites following the treatment with cytotoxic drugs.[19][20]

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.[21]

Mutation in WT1 causes predisposition to

hernias.[22]

As a drug target

A

acquired immune response against WT1 is in clinical trials for various cancers.[23][24][25] T cell therapies (TCR-T) are also being tested in clinical trials for leukemia.[26][27]

Disease monitoring

WT1 gene is overexpressed in case of

overexpressed WT1 and for in specific cases WT1 monitoring can be used even in patients diagnosed with those types of cancer.[29]

Interactions

WT1 has been shown to

interact with TET2,[17] U2AF2,[30] PAWR,[31] UBE2I[32] and WTAP.[33] In combination with Cited2 activates WT1 the Steroidogenic factor 1[34]

RNA editing

There is some evidence for

mRNA. As with alternative splicing of the gene RNA editing increases the number of isoforms of this protein.[35][36]

Editing is tissue specific and developmentally regulated. Editing shown to be restricted in testis and kidney in the rat.[35] Editing of this gene product has been found to occur in mice and rats as well as humans.[35][37]

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)[35]

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.[35]

Effects of editing

RNA editing results in an alternative amino acid being translated.[35] The changes in amino acid occur in a region identified as a domain involved in transcription activation function.[38]

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.[37]

Experimental models

WT1 gene can be found as well in the

embryonic stages. This suggests that WT1 is unconditionally required for a proper kidney formation and development.[39]

Apart from that, the WT1

swelling and lymph circulation were described. Due to those defects, the mouse died before it was even born.[39]

Mouse model is used to study some specific disorder connected with WT1 expression, too, such as

hematopoietic progenitors and precursors.[41]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000184937 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000016458 – Ensembl, May 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. S2CID 39909491
    .
  6. S2CID 29092372
    .
  7. ^
    S2CID 4235306
    .
  8. PMID 2173145
    .
  9. ^ "Entrez Gene: WT1 Wilms tumor 1".
  10. PMID 17634147
    .
  11. ^ RESERVED IU. "Orphanet: Nephroblastoma". www.orpha.net. Retrieved 2019-05-06.{{cite web}}: CS1 maint: numeric names: authors list (link)
  12. S2CID 221754031
    .
  13. PMID 1671709
    .
  14. PMID 1317572
    .
  15. PMID 22789581
    . Retrieved 2019-01-28.
  16. PMID 25482556
    .
  17. ^
    PMID 25601757
    .
  18. PMID 25699704
    .
  19. PMID 20122396
    .
  20. PMID 20122399
    .
  21. ISBN 978-1-84110-100-2
    .
  22. PMID 26686553
    .
  23. ^ "SELLAS Life Sciences Announces Positive WT1 Cancer Vaccine (galinpepimut-S) Clinical Results at the 13th International Conference of the International Mesothelioma Interest Group (iMig)". Archived from the original on 2016-06-04. Retrieved 2016-05-08.
  24. ^ Pleural mesothelioma WT1 vaccine is renamed "galinpepimut-S"
  25. PMID 16918359
    .
  26. PMID 31235963
    .
  27. PMID 28860210
    .
  28. S2CID 6677442
    .
  29. ^
    PMID 20395243
    .
  30. PMID 9784496
    .
  31. PMID 8943350
    .
  32. PMID 8798754
    .
  33. PMID 11001926
    .
  34. PMID 17537799
    .
  35. ^
    PMID 7926762
    .
  36. PMID 12665546
    .
  37. ^
    PMID 11065340
    .
  38. PMID 8486616
    .
  39. ^
    S2CID 2019375
    .
  40. PMID 10942395
    .
  41. PMID 17525726
    .

Further reading

External links
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