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WT1 has been shown to [[Protein-protein interaction|interact]] with [[U2AF2]],<ref name="pmid9784496">{{cite journal | author = 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 Dev. | volume = 12 | issue = 20 | pages = 3217–25 | year = 1998 | month = October | pmid = 9784496 | pmc = 317218 | doi = 10.1101/gad.12.20.3217| url = | issn = }}</ref> [[PAWR]],<ref name="pmid8943350">{{cite journal | author = 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 = Mol. Cell. Biol. | volume = 16 | issue = 12 | pages = 6945–56 | year = 1996 | month = December | pmid = 8943350 | pmc = 231698 | doi = | url = | issn = }}</ref> [[UBE2I]]<ref name="pmid8798754">{{cite journal | author = 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 = J. Biol. Chem. | volume = 271 | issue = 40 | pages = 24811–6 | year = 1996 | month = October | pmid = 8798754 | doi = 10.1074/jbc.271.40.24811| url = | issn = }}</ref> and [[WTAP (gene)|WTAP]].<ref name="pmid11001926">{{cite journal | author = Little NA, Hastie ND, Davies RC | title = Identification of WTAP, a novel Wilms' tumour 1-associating protein | journal = Hum. Mol. Genet. | volume = 9 | issue = 15 | pages = 2231–9 | year = 2000 | month = September | pmid = 11001926 | doi = 10.1093/oxfordjournals.hmg.a018914| url = | issn = }}</ref>
WT1 has been shown to [[Protein-protein interaction|interact]] with [[U2AF2]],<ref name="pmid9784496">{{cite journal | author = 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 Dev. | volume = 12 | issue = 20 | pages = 3217–25 | year = 1998 | month = October | pmid = 9784496 | pmc = 317218 | doi = 10.1101/gad.12.20.3217| url = | issn = }}</ref> [[PAWR]],<ref name="pmid8943350">{{cite journal | author = 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 = Mol. Cell. Biol. | volume = 16 | issue = 12 | pages = 6945–56 | year = 1996 | month = December | pmid = 8943350 | pmc = 231698 | doi = | url = | issn = }}</ref> [[UBE2I]]<ref name="pmid8798754">{{cite journal | author = 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 = J. Biol. Chem. | volume = 271 | issue = 40 | pages = 24811–6 | year = 1996 | month = October | pmid = 8798754 | doi = 10.1074/jbc.271.40.24811| url = | issn = }}</ref> and [[WTAP (gene)|WTAP]].<ref name="pmid11001926">{{cite journal | author = Little NA, Hastie ND, Davies RC | title = Identification of WTAP, a novel Wilms' tumour 1-associating protein | journal = Hum. Mol. Genet. | volume = 9 | issue = 15 | pages = 2231–9 | year = 2000 | month = September | pmid = 11001926 | doi = 10.1093/oxfordjournals.hmg.a018914| url = | issn = }}</ref>

==Zinc Finger domain==
The WT1 gene [[product (chemistry)|product]] shows similarity to the [[zinc finger]]s of the [[mammalia|mammalian]] [[cell growth|growth]] regulated early growth response protein 1 ([[EGR1]]) and ([[EGR2]]) [[protein]]s.<ref name="pmid17634147">{{cite journal| author=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 Res | year= 2007 | volume= 9 | issue= 4 | pages= R43 | pmid=17634147 | doi=10.1186/bcr1743 | pmc=PMC2206716 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17634147 }} </ref>


==Rna Editing==
==Rna Editing==

Revision as of 15:57, 3 July 2012

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

Template:PBB Wilms tumor protein is a protein that in humans is encoded by the WT1 gene.[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]

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 is 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. [6][7][3][8]

Degradation

The serine protease HtrA2 binds to WT1 and it cleaves WT1 at multiple sites following the treatment with cytotoxic drugs.[9][10]

Interactions

WT1 has been shown to interact with U2AF2,[11] PAWR,[12] UBE2I[13] and WTAP.[14]

Zinc Finger domain

The WT1 gene product shows similarity to the zinc fingers of the mammalian growth regulated early growth response protein 1 (EGR1) and (EGR2) proteins.[15]

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.[16][17]

Editing Type

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.[16]

Editing Site

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)[16]

Regulation

Editing is tissue specific and developmentally regulated.Editing shown to be restricted in testis and kidney in the rat.[16]

Conservation

Editing of this gene product has been found to occur in mice and rats as well as humans.[16][18]

Effects of editing

Structure

Rna editing results in an alternative amino acid being translated.[16] The changes in amino acid occur in a region identified as a domain involved in transcription activation function.[19]

Function

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.[18]

References

  1. ^ Burgin AB, Parodos K, Lane DJ, Pace NR (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ a b Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) Cite error: The named reference "pmid2154702" was defined multiple times with different content (see the help page).
  4. ^ Huang A, Campbell CE, Bonetta L, McAndrews-Hill MS, Chilton-MacNeill S, Coppes MJ, Law DJ, Feinberg AP, Yeger H, Williams BR (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ "Entrez Gene: WT1 Wilms tumor 1".
  6. ^ 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. {{cite journal}}: Unknown parameter |month= ignored (help)
  7. ^ Buckler AJ, Pelletier J, Haber DA, Glaser T, Housman DE (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Little MH, Prosser J, Condie A, Smith PJ, Van Heyningen V, Hastie ND (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Essafi A, Hastie ND (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ Hartkamp J, Carpenter B, Roberts SG (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ Davies RC, Calvio C, Bratt E, Larsson SH, Lamond AI, Hastie ND (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C, Haber DA, Licht JD, Sugrue SP, Roberts T, Rangnekar VM, Shi Y (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Wang ZY, Qiu QQ, Seufert W, Taguchi T, Testa JR, Whitmore SA, Callen DF, Welsh D, Shenk T, Deuel TF (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  14. ^ Little NA, Hastie ND, Davies RC (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ 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.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  16. ^ a b c d e f Sharma PM, Bowman M, Madden SL, Rauscher FJ, Sukumar S (1994). "RNA editing in the Wilms' tumor susceptibility gene, WT1". Genes Dev. 8 (6): 720–31. PMID 7926762. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Wagner KD, Wagner N, Schedl A (2003). "The complex life of WT1". J. Cell. Sci. 116 (Pt 9): 1653–8. doi:10.1242/jcs.00405. PMID 12665546. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ a b Mrowka C, Schedl A (2000). "Wilms' tumor suppressor gene WT1: from structure to renal pathophysiologic features". J. Am. Soc. Nephrol. 11 Suppl 16: S106–15. PMID 11065340. {{cite journal}}: Unknown parameter |month= ignored (help)
  19. ^ Wang ZY, Qiu QQ, Deuel TF (1993). "The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains". J. Biol. Chem. 268 (13): 9172–5. PMID 8486616. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

Further reading

Template:PBB Further reading

External links

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