WT1

WT1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1XF7, 2JP9, 2JPA, 2PRT, 3HPJ, 3MYJ, 4R2E, 4R2P, 4R2Q, 4R2R, 4R2S, 4WUU
Identifiers
Aliases	WT1, AEWS-GUD, NPHS4, WAGR, WIT-2, WT33, Wilms tumor 1
External IDs	MGI: 98968 HomoloGene: 11536 GeneCards: WT1
Gene location (Human) Chr. Chromosome 11 (human)[1] Band No data available Start 32,387,775 bp[1] End 32,435,630 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band No data available Start 105,126,529 bp[2] End 105,173,616 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • sequence-specific DNA binding • DNA binding • transcription factor activity, sequence-specific DNA binding • zinc ion binding • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • C2H2 zinc finger domain binding • metal ion binding • protein binding • RNA binding • nucleic acid binding • transcription regulatory region DNA binding • double-stranded methylated DNA binding • hemi-methylated DNA-binding Cellular component • cytoplasm • nuclear speck • nucleoplasm • nucleolus • nucleus • cytosol Biological process • germ cell development • adrenal cortex formation • ureteric bud development • negative regulation of translation • male gonad development • male genitalia development • regulation of transcription, DNA-templated • epithelial cell differentiation • glomerular basement membrane development • diaphragm development • kidney development • regulation of transcription from RNA polymerase II promoter • posterior mesonephric tubule development • visceral serous pericardium development • metanephric epithelium development • negative regulation of apoptotic process • glomerulus development • negative regulation of transcription from RNA polymerase II promoter • adrenal gland development • transcription, DNA-templated • positive regulation of metanephric ureteric bud development • vasculogenesis • 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 • sex determination • negative regulation of cell growth • RNA splicing • 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 • 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 proliferation • mesenchymal to epithelial transition • negative regulation of metanephric glomerular mesangial cell proliferation • positive regulation of transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • glomerular visceral epithelial cell differentiation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	7490	22431
Ensembl	ENSG00000184937	ENSMUSG00000016458
UniProt	P19544 Q6PI38	P22561
RefSeq (mRNA)	NM_024426 NM_000378 NM_001198551 NM_001198552 NM_024424 NM_024425	NM_144783
RefSeq (protein)	NP_000369 NP_001185480 NP_001185481 NP_077742 NP_077744 NP_000369.3 NP_001185480.1 NP_001185481.1 NP_077742.2 NP_077744.3	n/a
Location (UCSC)	Chr 11: 32.39 – 32.44 Mb	Chr 11: 105.13 – 105.17 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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

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.^[9]

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.^[10]

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.^{[7][11][12][13]}

WT1 is mutated in a mutually exclusive manner with TET2, IDH1, and IDH2 in acute myeloid leukemia.^[14] 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,^[15] representing an important feature of a new regulatory WIT pathway linked to the development of AML.^[16]

The serine protease HtrA2 binds to WT1 and it cleaves WT1 at multiple sites following the treatment with cytotoxic drugs.^[17][18]

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.^[19]

As a drug target

WT1 has been ranked by the National Cancer Institute (NCI) as the Number 1 target for cancer immunotherapy.^[20][21]

A vaccine that induces an innate immune response against WT1 is in clinical trials for various cancers.^[20][21][22]

Interactions

WT1 has been shown to interact with TET2,^[15] U2AF2,^[23] PAWR,^[24] UBE2I^[25] and WTAP.^[26] In combination with Cited2 activates WT1 the Steroidogenic factor 1^[27]

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.^[28][29]

Editing is tissue specific and developmentally regulated. Editing shown to be restricted in testis and kidney in the rat.^[28] Editing of this gene product has been found to occur in mice and rats as well as humans.^[28][30]

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)^[28]

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.^[28]

Effects of editing

RNA editing results in an alternative amino acid being translated.^[28] The changes in amino acid occur in a region identified as a domain involved in transcription activation function.^[31]

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.^[30]

References

Further reading

External links

• GeneReviews/NCBI/NIH/UW entry on Aniridia
• OMIM entries on Aniridia
• GeneReviews/NIH/NCBI/UW entry on Wilms Tumor Overview