View source for WT1

{{Infobox_gene}}
'''Wilms tumor protein''' is a [[protein]] that in humans is encoded by the ''WT1'' [[gene]] on chromosome 11p.<ref name="pmid2406020">{{cite journal | vauthors = Burgin AB, Parodos K, Lane DJ, Pace NR | title = The excision of intervening sequences from Salmonella 23S ribosomal RNA | journal = Cell | volume = 60 | issue = 3 | pages = 405–14 | date = Feb 1990 | pmid = 2406020 | doi = 10.1016/0092-8674(90)90592-3 }}</ref><ref name="pmid2154335">{{cite journal | vauthors = Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH | title = Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus | journal = Cell | volume = 60 | issue = 3 | pages = 509–20 | date = Feb 1990 | pmid = 2154335 | doi = 10.1016/0092-8674(90)90601-A }}</ref><ref name="pmid2154702">{{cite journal | vauthors = Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA | title = Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping | journal = Nature | volume = 343 | issue = 6260 | pages = 774–8 | date = Feb 1990 | pmid = 2154702 | doi = 10.1038/343774a0 }}</ref><ref name="pmid2173145">{{cite journal | vauthors = Huang A, Campbell CE, Bonetta L, McAndrews-Hill MS, Chilton-MacNeill S, Coppes MJ, Law DJ, Feinberg AP, Yeger H, Williams BR | title = Tissue, developmental, and tumor-specific expression of divergent transcripts in Wilms tumor | journal = Science | volume = 250 | issue = 4983 | pages = 991–4 | date = Nov 1990 | pmid = 2173145 | doi = 10.1126/science.2173145 }}</ref>

== 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.<ref>{{cite web | title = Entrez Gene: WT1 Wilms tumor 1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7490| accessdate = }}</ref>

== Structure ==

{{Infobox protein family
| Symbol = WT1
| Name = WT1
| image = 
| width = 
| caption = structure of the wilms tumor suppressor protein zinc finger domain bound to dna
| Pfam = PF02165
| Pfam_clan =  
| InterPro = IPR000976
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 
| OPM family = 
| OPM protein = 
| CAZy = 
| CDD = 
| align = left
}}
The WT1 gene [[product (chemistry)|product]] shows similarity to the [[zinc finger]]s of the [[mammalia]]n [[cell growth|growth]] regulated early growth response protein 1 ([[EGR1]]) and ([[EGR2]]) [[protein]]s.<ref name="pmid17634147">{{cite journal | vauthors = Han Y, San-Marina S, Yang L, Khoury H, Minden MD | title = 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 | journal = Breast Cancer Research | volume = 9 | issue = 4 | pages = R43 | year = 2007 | pmid = 17634147 | pmc = 2206716 | doi = 10.1186/bcr1743 }}</ref>
{{clear|left}}

== 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 [[Tumor|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.<ref name="pmid2154702" /><ref name="pmid8393820">{{cite journal | vauthors = Rauscher FJ | title = The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor | journal = FASEB Journal | volume = 7 | issue = 10 | pages = 896–903 | date = Jul 1993 | pmid = 8393820 | doi =  }}</ref><ref name="pmid1671709">{{cite journal | vauthors = Buckler AJ, Pelletier J, Haber DA, Glaser T, Housman DE | title = Isolation, characterization, and expression of the murine Wilms' tumor gene (WT1) during kidney development | journal = Molecular and Cellular Biology | volume = 11 | issue = 3 | pages = 1707–12 | date = Mar 1991 | pmid = 1671709 | pmc = 369476 | doi =  10.1128/mcb.11.3.1707}}</ref><ref name="pmid1317572">{{cite journal | vauthors = Little MH, Prosser J, Condie A, Smith PJ, Van Heyningen V, Hastie ND | title = Zinc finger point mutations within the WT1 gene in Wilms tumor patients | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 11 | pages = 4791–5 | date = Jun 1992 | pmid = 1317572 | pmc = 49173 | doi = 10.1073/pnas.89.11.4791 }}</ref>

WT1 is mutated in a [[Mutual exclusivity|mutually exclusive]] manner with [[TET2]], [[IDH1]], and [[IDH2]] in [[acute myeloid leukemia]].<ref name="pmid25482556">{{cite journal | vauthors = 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 | title = DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia | journal = Cell Reports | volume = 9 | issue = 5 | pages = 1841–55 | date = Dec 2014 | pmid = 25482556 | doi = 10.1016/j.celrep.2014.11.004 | pmc=4267494}}</ref> 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,<ref name="pmid25601757">{{cite journal | vauthors = 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 | title = WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation | journal = Molecular Cell | volume = 57 | issue = 4 | pages = 662–73 | date = Feb 2015 | pmid = 25601757 | doi = 10.1016/j.molcel.2014.12.023 | pmc=4336627}}</ref> representing an important feature of a new regulatory WIT pathway linked to the development of AML.<ref name="pmid25699704">{{cite journal | vauthors = Sardina JL, Graf T | title = A new path to leukemia with WIT | journal = Molecular Cell | volume = 57 | issue = 4 | pages = 573–4 | date = Feb 2015 | pmid = 25699704 | doi = 10.1016/j.molcel.2015.02.005 }}</ref>

The serine protease [[HtrA serine peptidase 2|HtrA2]] binds to WT1 and it cleaves WT1 at multiple sites following the treatment with cytotoxic drugs.<ref name="pmid20122396">{{cite journal | vauthors = Essafi A, Hastie ND | title = WT1 the oncogene: a tale of death and HtrA | journal = Molecular Cell | volume = 37 | issue = 2 | pages = 153–5 | date = Jan 2010 | pmid = 20122396 | doi = 10.1016/j.molcel.2010.01.010 }}</ref><ref name="pmid20122399">{{cite journal | vauthors = Hartkamp J, Carpenter B, Roberts SG | title = The Wilms' tumor suppressor protein WT1 is processed by the serine protease HtrA2/Omi | journal = Molecular Cell | volume = 37 | issue = 2 | pages = 159–71 | date = Jan 2010 | pmid = 20122399 | pmc = 2815029 | doi = 10.1016/j.molcel.2009.12.023 }}</ref>

Using [[immunohistochemistry]], WT1 protein can be demonstrated in the cell nuclei of 75% of [[mesothelioma]]s and in 93% of [[ovarian cancer#Classification|ovarian serous carcinoma]]s, 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 [[cytoplasm]]ic proteins in a variety of benign and malignant cells, so that only nuclear staining can be considered diagnostic.<ref name=Leong>{{cite book | vauthors = Leong AS, Cooper K, Leong FJ | year = 2003 | title = Manual of Diagnostic Cytology | edition = 2 | publisher = Greenwich Medical Media, Ltd. | pages = 447–448 | isbn = 1-84110-100-1 }}</ref>

===As a drug target===
WT1 has been ranked by the [[National Cancer Institute]] (NCI) as the Number 1 target for [[cancer immunotherapy]].<ref name=Sellas2016-05>[http://sellaslifesciences.com/2016/05/sellas-life-sciences-announces-positive-wt1-cancer-vaccine-galinpepimut-s-clinical-results-at-the-13th-international-conference-of-the-international-mesothelioma-interest-group-imig/ SELLAS Life Sciences Announces Positive WT1 Cancer Vaccine (galinpepimut-S) Clinical Results at the 13th International Conference of the International Mesothelioma Interest Group (iMig)]</ref><ref name=mymeso2016>[http://www.mymeso.org/2016/04/08/pleural-mesothelioma-wt1-vaccine-is-renamed-galinpepimut-s/ Pleural mesothelioma WT1 vaccine is renamed "galinpepimut-S"]</ref>

A [[vaccine]] that induces an [[innate immune response]] against WT1 is in [[clinical trial]]s for various cancers.<ref name=Sellas2016-05/><ref name=mymeso2016/><ref name=Oka2006>{{cite journal | pmid = 16918359 | volume=13 | title=Development of WT1 peptide cancer vaccine against hematopoietic malignancies and solid cancers | journal=Curr Med Chem | pages=2345–52 | vauthors=Oka Y, Tsuboi A, Kawakami M, Elisseeva OA, Nakajima H, Udaka K, Kawase I, Oji Y, Sugiyama H}}</ref>

== Interactions ==

WT1 has been shown to [[Protein-protein interaction|interact]] with [[Tet methylcytosine dioxygenase 2|TET2]],<ref name="pmid25601757"/> [[U2AF2]],<ref name="pmid9784496">{{cite journal | vauthors = Davies RC, Calvio C, Bratt E, Larsson SH, Lamond AI, Hastie ND | title = WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes | journal = Genes & Development | volume = 12 | issue = 20 | pages = 3217–25 | date = Oct 1998 | pmid = 9784496 | pmc = 317218 | doi = 10.1101/gad.12.20.3217 }}</ref> [[PAWR]],<ref name="pmid8943350">{{cite journal | vauthors = Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, Rangnekar VM, Shi Y | title = A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1 | journal = Molecular and Cellular Biology | volume = 16 | issue = 12 | pages = 6945–56 | date = Dec 1996 | pmid = 8943350 | pmc = 231698 | doi =  10.1128/mcb.16.12.6945}}</ref> [[UBE2I]]<ref name="pmid8798754">{{cite journal | vauthors = Wang ZY, Qiu QQ, Seufert W, Taguchi T, Testa JR, Whitmore SA, Callen DF, Welsh D, Shenk T, Deuel TF | title = Molecular cloning of the cDNA and chromosome localization of the gene for human ubiquitin-conjugating enzyme 9 | journal = The Journal of Biological Chemistry | volume = 271 | issue = 40 | pages = 24811–6 | date = Oct 1996 | pmid = 8798754 | doi = 10.1074/jbc.271.40.24811 }}</ref> and [[WTAP (gene)|WTAP]].<ref name="pmid11001926">{{cite journal | vauthors = Little NA, Hastie ND, Davies RC | title = Identification of WTAP, a novel Wilms' tumour 1-associating protein | journal = Human Molecular Genetics | volume = 9 | issue = 15 | pages = 2231–9 | date = Sep 2000 | pmid = 11001926 | doi = 10.1093/oxfordjournals.hmg.a018914 }}</ref> In combination with Cited2 activates WT1 the [[Steroidogenic factor 1]]<ref name=pmid17537799>{{cite journal| vauthors = Val P, ((Martinez-Barbera J-P)), Swain A | title= Adrenal development is initiated by Cited2 and Wt1 through modulation of Sf-1 dosage | journal=Development | volume= 134 | issue= 12| pages = 2349–58| date=Jun 2007| pmid=17537799 | doi=10.1242/dev.004390 }}</ref>

== 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.<ref name="pmid7926762">{{cite journal | vauthors = Sharma PM, Bowman M, Madden SL, Rauscher FJ, Sukumar S | title = RNA editing in the Wilms' tumor susceptibility gene, WT1 | journal = Genes & Development | volume = 8 | issue = 6 | pages = 720–31 | date = Mar 1994 | pmid = 7926762 | doi = 10.1101/gad.8.6.720 | url = http://www.genesdev.org/cgi/pmidlookup?view=long&pmid=7926762 }}</ref><ref name="pmid12665546">{{cite journal | vauthors = Wagner KD, Wagner N, Schedl A | title = The complex life of WT1 | journal = Journal of Cell Science | volume = 116 | issue = Pt 9 | pages = 1653–8 | date = May 2003 | pmid = 12665546 | doi = 10.1242/jcs.00405 | url = http://jcs.biologists.org/cgi/pmidlookup?view=long&pmid=12665546 }}</ref>

Editing is tissue specific and developmentally regulated. Editing shown to be restricted in testis and kidney in the rat.<ref name="pmid7926762"/> Editing of this gene product has been found to occur in mice and rats as well as humans.<ref name="pmid7926762"/><ref name="pmid11065340">{{cite journal | vauthors = Mrowka C, Schedl A | title = Wilms' tumor suppressor gene WT1: from structure to renal pathophysiologic features | journal = Journal of the American Society of Nephrology | volume = 11 Suppl 16 | issue =  | pages = S106-15 | date = Nov 2000 | pmid = 11065340 | doi =  | url = http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=11065340 }}</ref>

=== 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)<ref name="pmid7926762"/>

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.<ref name="pmid7926762"/>

=== Effects of editing ===

RNA editing results in an alternative amino acid being translated.<ref name="pmid7926762"/> The changes in amino acid occur in a region identified as a domain involved in transcription activation function.<ref name="pmid8486616">{{cite journal | vauthors = Wang ZY, Qiu QQ, Deuel TF | title = The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains | journal = The Journal of Biological Chemistry | volume = 268 | issue = 13 | pages = 9172–5 | date = May 1993 | pmid = 8486616 | doi =  | url = http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8486616 }}</ref>

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]].<ref name="pmid11065340"/>

== References ==
{{reflist|35em}}

== Further reading ==
{{refbegin|35em}}
* {{cite journal | vauthors = Haber DA, Buckler AJ | title = WT1: a novel tumor suppressor gene inactivated in Wilms' tumor | journal = The New Biologist | volume = 4 | issue = 2 | pages = 97–106 | date = Feb 1992 | pmid = 1313285 | doi =  }}
* {{cite journal | vauthors = Rauscher FJ | title = The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor | journal = FASEB Journal | volume = 7 | issue = 10 | pages = 896–903 | date = Jul 1993 | pmid = 8393820 | doi =  }}
* {{cite journal | vauthors = Lee SB, Haber DA | title = Wilms tumor and the WT1 gene | journal = Experimental Cell Research | volume = 264 | issue = 1 | pages = 74–99 | date = Mar 2001 | pmid = 11237525 | doi = 10.1006/excr.2000.5131 }}
* {{cite journal | vauthors = Scharnhorst V, van der Eb AJ, Jochemsen AG | title = WT1 proteins: functions in growth and differentiation | journal = Gene | volume = 273 | issue = 2 | pages = 141–61 | date = Aug 2001 | pmid = 11595161 | doi = 10.1016/S0378-1119(01)00593-5 }}
* {{cite journal | vauthors = Lim HN, Hughes IA, Hawkins JR | title = Clinical and molecular evidence for the role of androgens and WT1 in testis descent | journal = Molecular and Cellular Endocrinology | volume = 185 | issue = 1–2 | pages = 43–50 | date = Dec 2001 | pmid = 11738793 | doi = 10.1016/S0303-7207(01)00631-1 }}
* {{cite journal | vauthors = Heathcott RW, Morison IM, Gubler MC, Corbett R, Reeve AE | title = A review of the phenotypic variation due to the Denys-Drash syndrome-associated germline WT1 mutation R362X | journal = Human Mutation | volume = 19 | issue = 4 | pages = 462 | date = Apr 2002 | pmid = 11933209 | doi = 10.1002/humu.9031 }}
* {{cite journal | vauthors = Wagner KD, Wagner N, Schedl A | title = The complex life of WT1 | journal = Journal of Cell Science | volume = 116 | issue = Pt 9 | pages = 1653–8 | date = May 2003 | pmid = 12665546 | doi = 10.1242/jcs.00405 }}
* {{cite journal | vauthors = Amini Nik S, Hohenstein P, Jadidizadeh A, Van Dam K, Bastidas A, Berry RL, Patek CE, Van der Schueren B, Cassiman JJ, Tejpar S | title = Upregulation of Wilms' tumor gene 1 (WT1) in desmoid tumors | journal = International Journal of Cancer | volume = 114 | issue = 2 | pages = 202–8 | date = Mar 2005 | pmid = 15540161 | doi = 10.1002/ijc.20717 }}
* {{cite journal | vauthors = Niaudet P, Gubler MC | title = WT1 and glomerular diseases | journal = Pediatric Nephrology | volume = 21 | issue = 11 | pages = 1653–60 | date = Nov 2006 | pmid = 16927106 | doi = 10.1007/s00467-006-0208-1 }}
* {{cite journal | vauthors = 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 | title = Upregulation of Wilms' tumour gene 1 (WT1) in uterine sarcomas | journal = European Journal of Cancer | volume = 43 | issue = 10 | pages = 1630–7 | date = Jul 2007 | pmid = 17531467 | doi = 10.1016/j.ejca.2007.04.008 }}
* {{cite journal | vauthors = Hohenstein P, Hastie ND | title = The many facets of the Wilms' tumour gene, WT1 | journal = Human Molecular Genetics | volume = 15 Spec No 2 | issue =  | pages = R196-201 | date = Oct 2006 | pmid = 16987884 | doi = 10.1093/hmg/ddl196 }}
{{refend}}

== External links ==
* [https://www.ncbi.nlm.nih.gov/books/NBK1360/  GeneReviews/NCBI/NIH/UW entry on Aniridia]
* [https://www.ncbi.nlm.nih.gov/omim/106210,194070,194072,607102,607108,106210,194070,194072,607102,607108 OMIM entries on Aniridia]
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=wilms-ov GeneReviews/NIH/NCBI/UW entry on Wilms Tumor Overview]

{{PDB Gallery|geneid=7490}}
{{Tumor suppressor genes}}
{{Transcription factors|g2}}