Summary: Wilm's tumour protein
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|Wilms tumor 1|
PDB rendering based on 1xf7.
|RNA expression pattern|
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.
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.
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.
Editing is tissue specific and developmentally regulated. Editing shown to be restricted in testis and kidney in the rat. Editing of this gene product has been found to occur in mice and rats as well as humans.
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)
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 consiting of 10 nucleotides before the editing site and four after the site.
Effects of editing
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.
- 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. doi:10.1016/0092-8674(90)90592-3. PMID 2406020.
- 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. doi:10.1016/0092-8674(90)90601-A. PMID 2154335.
- 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. doi:10.1038/343774a0. PMID 2154702.
- 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. doi:10.1126/science.2173145. PMID 2173145.
- "Entrez Gene: WT1 Wilms tumor 1".
- 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. doi:10.1186/bcr1743. PMC 2206716. PMID 17634147.
- 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. PMID 8393820.
- 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. PMC 369476. PMID 1671709.
- 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. PMC 49173. PMID 1317572.
- Essafi A, Hastie ND (January 2010). "WT1 the oncogene: a tale of death and HtrA". Mol. Cell 37 (2): 153–5. doi:10.1016/j.molcel.2010.01.010. PMID 20122396.
- 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. doi:10.1016/j.molcel.2009.12.023. PMC 2815029. PMID 20122399.
- Leong AS-Y, Cooper K, Leong FJW-M (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. pp. 447–448. ISBN 1-84110-100-1.
- 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. doi:10.1101/gad.12.20.3217. PMC 317218. PMID 9784496.
- 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. PMC 231698. PMID 8943350.
- 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. doi:10.1074/jbc.271.40.24811. PMID 8798754.
- 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. doi:10.1093/oxfordjournals.hmg.a018914. PMID 11001926.
- Sharma PM, Bowman M, Madden SL, Rauscher FJ, Sukumar S (March 1994). "RNA editing in the Wilms' tumor susceptibility gene, WT1". Genes Dev. 8 (6): 720–31. PMID 7926762.
- Wagner KD, Wagner N, Schedl A (May 2003). "The complex life of WT1". J. Cell. Sci. 116 (Pt 9): 1653–8. doi:10.1242/jcs.00405. PMID 12665546.
- Mrowka C, Schedl A (November 2000). "Wilms' tumor suppressor gene WT1: from structure to renal pathophysiologic features". J. Am. Soc. Nephrol. 11 Suppl 16: S106–15. PMID 11065340.
- Wang ZY, Qiu QQ, Deuel TF (May 1993). "The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains". J. Biol. Chem. 268 (13): 9172–5. PMID 8486616.
- Haber DA, Buckler AJ (1992). "WT1: a novel tumor suppressor gene inactivated in Wilms' tumor.". New Biol. 4 (2): 97–106. PMID 1313285.
- Rauscher FJ (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. PMID 8393820.
- Lee SB, Haber DA (2001). "Wilms tumor and the WT1 gene.". Exp. Cell Res. 264 (1): 74–99. doi:10.1006/excr.2000.5131. PMID 11237525.
- Scharnhorst V, van der Eb AJ, Jochemsen AG (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 (2003). "Clinical and molecular evidence for the role of androgens and WT1 in testis descent.". Mol. Cell. Endocrinol. 185 (1–2): 43–50. doi:10.1016/S0303-7207(01)00631-1. PMID 11738793.
- Heathcott RW, Morison IM, Gubler MC, et al. (2002). "A review of the phenotypic variation due to the Denys-Drash syndrome-associated germline WT1 mutation R362X". Hum. Mutat. 19 (4): 462. doi:10.1002/humu.9031. PMID 11933209.
- Wagner KD, Wagner N, Schedl A (2004). "The complex life of WT1". J. Cell. Sci. 116 (Pt 9): 1653–8. doi:10.1242/jcs.00405. PMID 12665546.
- Amini Nik S, Hohenstein P (2005). "Upregulation of Wilms' tumor gene 1 (WT1) in desmoid tumors". Int J Cancer 114 (2): 202–8. doi:10.1002/ijc.20717. PMID 15540161.
- Niaudet P, Gubler MC (2007). "WT1 and glomerular diseases". Pediatr. Nephrol. 21 (11): 1653–60. doi:10.1007/s00467-006-0208-1. PMID 16927106.
- Coosemans A, Amini Nik S (2007). "Upregulation of Wilms' tumour gene 1 (WT1) in uterine sarcomas". Eur J Cancer 43 (10): 1630–37. doi:10.1016/j.ejca.2007.04.008. PMID 17531467.
- Hohenstein P, Hastie ND (2006). "The many facets of the Wilms' tumour gene, WT1". Hum. Mol. Genet. 15 Spec No 2: R196–201. doi:10.1093/hmg/ddl196. PMID 16987884.
- GeneReviews/NCBI/NIH/UW entry on Aniridia
- OMIM entries on Aniridia
- GeneReviews/NIH/NCBI/UW entry on Wilms Tumor Overview
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Wilm's tumour protein Provide feedback
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External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000976Wilm's tumour (WT) is an embryonal malignancy of the kidney, affecting around 1 in 10,000 infants. It occurs in both sporadic and hereditary forms. Inactivation of WT1 is one of the causes of Wilm's tumour. Defects in the WT1 gene are also associated with Denys-Drash Syndrome (DDS), which is characterised by typical nephropathy and genital abnormalities. The WT1 gene product shows similarity to the zinc fingers of the mammalian growth regulated EGR1 and EGR2 proteins [PUBMED:8393820, PUBMED:1671709, PUBMED:2154702, PUBMED:1317572].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||nucleus (GO:0005634)|
|Biological process||regulation of transcription, DNA-dependent (GO:0006355)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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a textual description of the architecture, e.g. Gla, EGF x 2, Trypsin.
This example describes an architecture with one
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EGFdomains, and finally a single
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We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...
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We make a range of alignments for each Pfam-A family:
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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.
1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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Curation and family details
This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Author:||Mian N, Bateman A|
|Number in seed:||8|
|Number in full:||147|
|Average length of the domain:||217.70 aa|
|Average identity of full alignment:||64 %|
|Average coverage of the sequence by the domain:||67.01 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||10|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
Colouring and labels
Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
Anomalies in the taxonomy tree
There are some situations that the sunburst tree cannot easily handle and for which we have work-arounds in place.
Missing taxonomic levels
Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
Too many species/sequences
For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the WT1 domain has been found. There are 6 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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