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A tumor suppressor and oncogene: the WT1 story

Leukemia volume 21, pages 868–876 (2007)Cite this article

A Corrigendum to this article was published on 20 June 2007

Abstract

The Wilms' tumor 1 (WT1) gene encodes a transcription factor important for normal cellular development and cell survival. The initial discovery of WT1 as the causative gene in an autosomal-recessive condition identified it as a tumor suppressor gene whose mutations are associated with urogenital disease and the development of kidney tumors. However, this view is not in keeping with the frequent finding of wild-type, full-length WT1 in human leukemia, breast cancer and several other cancers including the majority of Wilms' tumors. Rather, these observations suggest that in those conditions, WT1 has an oncogenic role in tumor formation. In this review, we explore the literature supporting both views of WT1 in human cancer and in particular human leukemias. To understand the mechanism by which WT1 can do this, we will also examine its functional activity as a transcription factor and the influence of protein partners on its dual behavior.

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References

  1. Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 1992; 69: 119–128.

    Article  CAS  PubMed  Google Scholar 

  2. Menke AL, van der Eb AJ, Jochemsen AG . The Wilms' tumor 1 gene: oncogene or tumor suppressor gene? Int Rev Cytol 1998; 181: 151–212.

    Article  CAS  PubMed  Google Scholar 

  3. Rivera MN, Haber DA . Wilms' tumour: connecting tumorigenesis and organ development in the kidney. Nat Rev Cancer 2005; 5: 699–712.

    Article  CAS  PubMed  Google Scholar 

  4. Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1990; 60: 509–520.

    Article  CAS  PubMed  Google Scholar 

  5. Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM, Housman DE . Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci USA 1991; 88: 9618–9622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Dallosso AR, Hancock AL, Brown KW, Williams AC, Jackson S, Malik K . Genomic imprinting at the WT1 gene involves a novel coding transcript (AWT1) that shows deregulation in Wilms' tumours. Hum Mol Genet 2004; 13: 405–415.

    Article  CAS  PubMed  Google Scholar 

  7. Reddy JC, Hosono S, Licht JD . The transcriptional effect of WT1 is modulated by choice of expression vector. J Biol Chem 1995; 270: 29976–29982.

    Article  CAS  PubMed  Google Scholar 

  8. Wang ZY, Qiu QQ, Huang J, Gurrieri M, Deuel TF . Products of alternatively spliced transcripts of the Wilms' tumor suppressor gene, wt1, have altered DNA binding specificity and regulate transcription in different ways. Oncogene 1995; 10: 415–422.

    CAS  PubMed  Google Scholar 

  9. Laity JH, Chung J, Dyson HJ, Wright PE . Alternative splicing of Wilms' tumor suppressor protein modulates DNA binding activity through isoform-specific DNA-induced conformational changes. Biochemistry 2000; 39: 5341–5348.

    Article  CAS  PubMed  Google Scholar 

  10. Han Y, San-Marina S, Liu J, Minden MD . Transcriptional activation of c-myc proto-oncogene by WT1 protein. Oncogene 2004; 23: 6933–6941.

    Article  CAS  PubMed  Google Scholar 

  11. Hewitt SM, Hamada S, McDonnell TJ, Rauscher III FJ, Saunders GF . Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor suppressor gene WT1. Cancer Res 1995; 55: 5386–5389.

    CAS  PubMed  Google Scholar 

  12. Heckman C, Mochon E, Arcinas M, Boxer LM . The WT1 protein is a negative regulator of the normal bcl-2 allele in t(14;18) lymphomas. J Biol Chem 1997; 272: 19609–19614.

    Article  CAS  PubMed  Google Scholar 

  13. Mayo MW, Wang CY, Drouin SS, Madrid LV, Marshall AF, Reed JC et al. WT1 modulates apoptosis by transcriptionally upregulating the bcl-2 proto-oncogene. EMBO J 1999; 18: 3990–4003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Little M, Wells C . A clinical overview of WT1 gene mutations. Hum Mutat 1997; 9: 209–225.

    Article  CAS  PubMed  Google Scholar 

  15. Little MH, Williamson KA, Mannens M, Kelsey A, Gosden C, Hastie ND et al. Evidence that WT1 mutations in Denys–Drash syndrome patients may act in a dominant-negative fashion. Hum Mol Genet 1993; 2: 259–264.

    Article  CAS  PubMed  Google Scholar 

  16. Little M, Holmes G, Bickmore W, van H, Hastie V N, Wainwright B . DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations. Hum Mol Genet 1995; 4: 351–358.

    Article  CAS  PubMed  Google Scholar 

  17. Klamt B, Koziell A, Poulat F, Wieacker P, Scambler P, Berta P et al. Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/−KTS splice isoforms. Hum Mol Genet 1998; 7: 709–714.

    Article  CAS  PubMed  Google Scholar 

  18. Smith SI, Down M, Boyd AW, Li CL . Expression of the Wilms' tumor suppressor gene, WT1, reduces the tumorigenicity of the leukemic cell line M1 in C.B-17 scid/scid mice. Cancer Res 2000; 60: 808–814.

    CAS  PubMed  Google Scholar 

  19. Fraizer G, Leahy R, Priyadarshini S, Graham K, Delacerda J, Diaz M . Suppression of prostate tumor cell growth in vivo by WT1, the Wilms' tumor suppressor gene. Int J Oncol 2004; 24: 461–471.

    CAS  PubMed  Google Scholar 

  20. Luo XN, Reddy JC, Yeyati PL, Idris AH, Hosono S, Haber DA et al. The tumor suppressor gene WT1 inhibits ras-mediated transformation. Oncogene 1995; 11: 743–750.

    CAS  PubMed  Google Scholar 

  21. Haber DA, Park S, Maheswaran S, Englert C, Re GG, Hazen-Martin DJ et al. WT1-mediated growth suppression of Wilms tumor cells expressing a WT1 splicing variant. Science 1993; 262: 2057–2059.

    Article  CAS  PubMed  Google Scholar 

  22. McMaster ML, Gessler M, Stanbridge EJ, Weissman BE . WT1 expression alters tumorigenicity of the G401 kidney-derived cell line. Cell Growth Differ 1995; 6: 1609–1617.

    CAS  PubMed  Google Scholar 

  23. Menke AL, Shvarts A, Riteco N, van Ham RC, van der Eb AJ, Jochemsen AG . Wilms' tumor 1-KTS isoforms induce p53-independent apoptosis that can be partially rescued by expression of the epidermal growth factor receptor or the insulin receptor. Cancer Res 1997; 57: 1353–1363.

    CAS  PubMed  Google Scholar 

  24. Englert C, Hou X, Maheswaran S, Bennett P, Ngwu C, Re GG et al. WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. EMBO J 1995; 14: 4662–4675.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Morrison DJ, English MA, Licht JD . WT1 induces apoptosis through transcriptional regulation of the proapoptotic Bcl-2 family member Bak. Cancer Res 2005; 65: 8174–8182.

    Article  CAS  PubMed  Google Scholar 

  26. Hosen N, Sonoda Y, Oji Y, Kimura T, Minamiguchi H, Tamaki H et al. Very low frequencies of human normal CD34+ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells. Br J Haematol 2002; 116: 409–420.

    Article  CAS  PubMed  Google Scholar 

  27. Baird PN, Simmons PJ . Expression of the Wilms' tumor gene (WT1) in normal hemopoiesis. Exp Hematol 1997; 25: 312–320.

    CAS  PubMed  Google Scholar 

  28. Alberta JA, Springett GM, Rayburn H, Natoli TA, Loring J, Kreidberg JA et al. Role of the WT1 tumor suppressor in murine hematopoiesis. Blood 2003; 101: 2570–2574.

    Article  CAS  PubMed  Google Scholar 

  29. King-Underwood L, Little S, Baker M, Clutterbuck R, Delassus S, Enver T et al. Wt1 is not essential for hematopoiesis in the mouse. Leuk Res 2005; 29: 803–812.

    Article  CAS  PubMed  Google Scholar 

  30. Nishida S, Hosen N, Shirakata T, Kanato K, Yanagihara M, Nakatsuka S et al. AML1-ETO rapidly induces acute myeloblastic leukemia in cooperation with the Wilms tumor gene, WT1. Blood 2006; 107: 3303–3312.

    Article  CAS  PubMed  Google Scholar 

  31. Ellisen LW, Carlesso N, Cheng T, Scadden DT, Haber DA . The Wilms tumor suppressor WT1 directs stage-specific quiescence and differentiation of human hematopoietic progenitor cells. EMBO J 2001; 20: 1897–1909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Svedberg H, Richter J, Gullberg U . Forced expression of the Wilms tumor 1 (WT1) gene inhibits proliferation of human hematopoietic CD34(+) progenitor cells. Leukemia 2001; 15: 1914–1922.

    Article  CAS  PubMed  Google Scholar 

  33. Svensson E, Eriksson H, Gekas C, Olofsson T, Richter J, Gullberg U . DNA-binding dependent and independent functions of WT1 protein during human hematopoiesis. Exp Cell Res 2005; 308: 211–221.

    Article  CAS  PubMed  Google Scholar 

  34. King-Underwood L, Renshaw J, Pritchard-Jones K . Mutations in the Wilms' tumor gene WT1 in leukemias. Blood 1996; 87: 2171–2179.

    Article  CAS  PubMed  Google Scholar 

  35. Valk PJ, Verhaak RG, Beijen MA, Erpelinck CA, Barjesteh van Waalwijk van Doorn-Khosrovani S, Boer JM et al. Prognostically useful gene-expression profiles in acute myeloid leukemia. New Engl J Med 2004; 350: 1617–1628.

    Article  CAS  PubMed  Google Scholar 

  36. Miyagi T, Ahuja H, Kubota T, Kubonishi I, Koeffler HP, Miyoshi I . Expression of the candidate Wilm's tumor gene, WT1, in human leukemia cells. Leukemia 1993; 7: 970–977.

    CAS  PubMed  Google Scholar 

  37. Miwa H, Beran M, Saunders GF . Expression of the Wilms' tumor gene (WT1) in human leukemias. Leukemia 1992; 6: 405–409.

    CAS  PubMed  Google Scholar 

  38. Menssen HD, Renkl HJ, Rodeck U, Maurer J, Notter M, Schwartz S et al. Presence of Wilms' tumor gene (wt1) transcripts and the WT1 nuclear protein in the majority of human acute leukemias. Leukemia 1995; 9: 1060–1067.

    CAS  PubMed  Google Scholar 

  39. Ostergaard M, Olesen LH, Hasle H, Kjeldsen E, Hokland P . WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukaemia patients - results from a single-centre study. Br J Haematol 2004; 125: 590–600.

    Article  CAS  PubMed  Google Scholar 

  40. Brieger J, Weidmann E, Fenchel K, Mitrou PS, Hoelzer D, Bergmann L . The expression of the Wilms' tumor gene in acute myelocytic leukemias as a possible marker for leukemic blast cells. Leukemia 1994; 8: 2138–2143.

    CAS  PubMed  Google Scholar 

  41. Schmid D, Heinze G, Linnerth B, Tisljar K, Kusec R, Geissler K et al. Prognostic significance of WT1 gene expression at diagnosis in adult de novo acute myeloid leukemia. Leukemia 1997; 11: 639–643.

    Article  CAS  PubMed  Google Scholar 

  42. Chiusa L, Francia di Celle P, Campisi P, Ceretto C, Marmont F, Pich A . Prognostic value of quantitative analysis of WT1 gene transcripts in adult acute lymphoblastic leukemia. Haematologica 2006; 91: 270–271.

    CAS  PubMed  Google Scholar 

  43. Tamaki H, Ogawa H, Ohyashiki K, Ohyashiki JH, Iwama H, Inoue K et al. The Wilms' tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia 1999; 13: 393–399.

    Article  CAS  PubMed  Google Scholar 

  44. Barragan E, Cervera J, Bolufer P, Ballester S, Martin G, Fernandez P et al. Prognostic implications of Wilms' tumor gene (WT1) expression in patients with de novo acute myeloid leukemia. Haematologica 2004; 89: 926–933.

    CAS  PubMed  Google Scholar 

  45. Bergmann L, Miething C, Maurer U, Brieger J, Karakas T, Weidmann E et al. High levels of Wilms' tumor gene (wt1) mRNA in acute myeloid leukemias are associated with a worse long-term outcome. Blood 1997; 90: 1217–1225.

    Article  CAS  PubMed  Google Scholar 

  46. Karakas T, Miething CC, Maurer U, Weidmann E, Ackermann H, Hoelzer D et al. The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia. Leukemia 2002; 16: 846–854.

    Article  CAS  PubMed  Google Scholar 

  47. Yamagami T, Sugiyama H, Inoue K, Ogawa H, Tatekawa T, Hirata M et al. Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis. Blood 1996; 87: 2878–2884.

    Article  CAS  PubMed  Google Scholar 

  48. Ito K, Oji Y, Tatsumi N, Shimizu S, Kanai Y, Nakazawa T et al. Antiapoptotic function of 17AA(+)WT1 (Wilms' tumor gene) isoforms on the intrinsic apoptosis pathway. Oncogene 2006; 25: 4217–4229.

    Article  CAS  PubMed  Google Scholar 

  49. Deuel TF, Guan LS, Wang ZY . Wilms' tumor gene product WT1 arrests macrophage differentiation of HL-60 cells through its zinc-finger domain. Biochem Biophys Res Commun 1999; 254: 192–196.

    Article  CAS  PubMed  Google Scholar 

  50. Gu W, Chen Z, Hu S, Shen H, Qiu G, Cao X . Changes in expression of WT1 isoforms during induced differentiation of the NB4 cell line. Haematologica 2005; 90: 403–405.

    CAS  PubMed  Google Scholar 

  51. Phelan SA, Lindberg C, Call KM . Wilms' tumor gene, WT1, mRNA is down-regulated during induction of erythroid and megakaryocytic differentiation of K562 cells. Cell Growth Differ 1994; 5: 677–686.

    CAS  PubMed  Google Scholar 

  52. Goodyer P, Dehbi M, Torban E, Bruening W, Pelletier J . Repression of the retinoic acid receptor-alpha gene by the Wilms' tumor suppressor gene product, wt1. Oncogene 1995; 10: 1125–1129.

    CAS  PubMed  Google Scholar 

  53. Svedberg H, Chylicki K, Baldetorp B, Rauscher III FJ, Gullberg U . Constitutive expression of the Wilms' tumor gene (WT1) in the leukemic cell line U937 blocks parts of the differentiation program. Oncogene 1998; 16: 925–932.

    Article  CAS  PubMed  Google Scholar 

  54. Svedberg H, Chylicki K, Gullberg U . Downregulation of Wilms' tumor gene (WT1) is not a prerequisite for erythroid or megakaryocytic differentiation of the leukemic cell line K562. Exp Hematol 1999; 27: 1057–1062.

    Article  CAS  PubMed  Google Scholar 

  55. Maheswaran S, Englert C, Bennett P, Heinrich G, Haber DA . The WT1 gene product stabilizes p53 and inhibits p53-mediated apoptosis. Genes Dev 1995; 9: 2143–2156.

    Article  CAS  PubMed  Google Scholar 

  56. Idelman G, Glaser T, Roberts Jr CT, Werner H . WT1-p53 interactions in insulin-like growth factor-I receptor gene regulation. J Biol Chem 2003; 278: 3474–3482.

    Article  CAS  PubMed  Google Scholar 

  57. Johnstone RW, See RH, Sells SF, Wang J, Muthukkumar S, Englert C et al. A novel repressor, par-4, modulates transcription and growth suppression functions of the Wilms' tumor suppressor WT1. Mol Cell Biol 1996; 16: 6945–6956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hossain A, Nixon M, Kuo MT, Saunders GF . N-terminally truncated WT1 protein with oncogenic properties overexpressed in leukemia. J Biol Chem 2006; 281: 28122–28130.

    Article  CAS  PubMed  Google Scholar 

  59. Sakamoto Y, Yoshida M, Semba K, Hunter T . Inhibition of the DNA-binding and transcriptional repression activity of the Wilms' tumor gene product, WT1, by cAMP-dependent protein kinase-mediated phosphorylation of Ser-365 and Ser-393 in the zinc finger domain. Oncogene 1997; 15: 2001–2012.

    Article  CAS  PubMed  Google Scholar 

  60. Ye Y, Raychaudhuri B, Gurney A, Campbell CE, Williams BR . Regulation of WT1 by phosphorylation: inhibition of DNA binding, alteration of transcriptional activity and cellular translocation. EMBO J 1996; 15: 5606–5615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Boyapati A, Kanbe E, Zhang DE . p53 alterations in myeloid leukemia. Acta Haematol 2004; 111: 100–106.

    Article  CAS  PubMed  Google Scholar 

  62. Devilard E, Bladou F, Ramuz O, Karsenty G, Dales JP, Gravis G et al. FGFR1 and WT1 are markers of human prostate cancer progression. BMC Cancer 2006; 6: 272.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Garg M, Moore H, Tobal K, Liu Yin JA . Prognostic significance of quantitative analysis of WT1 gene transcripts by competitive reverse transcription polymerase chain reaction in acute leukaemia. Br J Haematol 2003; 123: 49–59.

    Article  CAS  PubMed  Google Scholar 

  64. Gaiger A, Schmid D, Heinze G, Linnerth B, Greinix H, Kalhs P et al. Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia. Leukemia 1998; 12: 1886–1894.

    Article  CAS  PubMed  Google Scholar 

  65. Sugiyama H . Cancer immunotherapy targeting Wilms' tumor gene WT1 product. Expert Rev Vaccines 2005; 4: 503–512.

    Article  CAS  PubMed  Google Scholar 

  66. Nyvold CG, Stentoft J, Braendstrup K, Melsvik D, Moestrup SK, Juhl-Christensen C et al. Wilms' tumor 1 mutation accumulated during therapy in acute myeloid leukemia: Biological and clinical implications. Leukemia 2006; 20: 2051–2054.

    Article  CAS  PubMed  Google Scholar 

  67. Lee SB, Huang K, Palmer R, Truong VB, Herzlinger D, Kolquist KA et al. The Wilms tumor suppressor WT1 encodes a transcriptional activator of amphiregulin. Cell 1999; 98: 663–673.

    Article  CAS  PubMed  Google Scholar 

  68. Harrington MA, Konicek B, Song A, Xia XL, Fredericks WJ, Rauscher III FJ . Inhibition of colony-stimulating factor-1 promoter activity by the product of the Wilms' tumor locus. J Biol Chem 1993; 268: 21271–21275.

    Article  CAS  PubMed  Google Scholar 

  69. Nichols KE, Re GG, Yan YX, Garvin AJ, Haber DA . WT1 induces expression of insulin-like growth factor 2 in Wilms' tumor cells. Cancer Res 1995; 55: 4540–4543.

    CAS  PubMed  Google Scholar 

  70. Ward A, Pooler JA, Miyagawa K, Duarte A, Hastie ND, Caricasole A . Repression of promoters for the mouse insulin-like growth factor II-encoding gene (Igf-2) by products of the Wilms' tumour suppressor gene wt1. Gene 1995; 167: 239–243.

    Article  CAS  PubMed  Google Scholar 

  71. Drummond IA, Madden SL, Rohwer-Nutter P, Bell GI, Sukhatme VP, Rauscher III FJ . Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1. Science 1992; 257: 674–678.

    Article  CAS  PubMed  Google Scholar 

  72. Wang ZY, Qiu QQ, Deuel TF . The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains. J Biol Chem 1993; 268: 9172–9175.

    Article  CAS  PubMed  Google Scholar 

  73. Wang ZY, Madden SL, Deuel TF, Rauscher III FJ . The Wilms' tumor gene product, WT1, represses transcription of the platelet-derived growth factor A-chain gene. J Biol Chem 1992; 267: 21999–22002.

    Article  CAS  PubMed  Google Scholar 

  74. Gashler AL, Bonthron DT, Madden SL, Rauscher III FJ, Collins T, Sukhatme VP . Human platelet-derived growth factor A chain is transcriptionally repressed by the Wilms tumor suppressor WT1. Proc Natl Acad Sci USA 1992; 89: 10984–10988.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Dey BR, Sukhatme VP, Roberts AB, Sporn MB, Rauscher III FJ, Kim SJ . Repression of the transforming growth factor-beta 1 gene by the Wilms' tumor suppressor WT1 gene product. Mol Endocrinol 1994; 8: 595–602.

    CAS  PubMed  Google Scholar 

  76. Zaia A, Fraizer GC, Piantanelli L, Saunders GF . Transcriptional regulation of the androgen signaling pathway by the Wilms' tumor suppressor gene WT1. Anticancer Res 2001; 21: 1–10.

    CAS  PubMed  Google Scholar 

  77. Webster NJ, Kong Y, Sharma P, Haas M, Sukumar S, Seely BL . Differential effects of Wilms tumor WT1 splice variants on the insulin receptor promoter. Biochem Mol Med 1997; 62: 139–150.

    Article  CAS  PubMed  Google Scholar 

  78. Werner H, Rauscher III FJ, Sukhatme VP, Drummond IA, Roberts Jr CT, LeRoith D . Transcriptional repression of the insulin-like growth factor I receptor (IGF-I-R) gene by the tumor suppressor WT1 involves binding to sequences both upstream and downstream of the IGF-I-R gene transcription start site. J Biol Chem 1994; 269: 12577–12582.

    Article  CAS  PubMed  Google Scholar 

  79. Werner H, Re GG, Drummond IA, Sukhatme VP, Rauscher III FJ, Sens DA et al. Increased expression of the insulin-like growth factor I receptor gene, IGF1R, in Wilms tumor is correlated with modulation of IGF1R promoter activity by the WT1 Wilms tumor gene product. Proc Natl Acad Sci USA 1993; 90: 5828–5832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. McCann S, Sullivan J, Guerra J, Arcinas M, Boxer LM . Repression of the c-myb gene by WT1 protein in T and B cell lines. J Biol Chem 1995; 270: 23785–23789.

    Article  CAS  PubMed  Google Scholar 

  81. Udtha M, Lee SJ, Alam R, Coombes K, Huff V . Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors. Oncogene 2003; 22: 3821–3826.

    Article  CAS  PubMed  Google Scholar 

  82. Loeb DM, Korz D, Katsnelson M, Burwell EA, Friedman AD, Sukumar S . Cyclin E is a target of WT1 transcriptional repression. J Biol Chem 2002; 277: 19627–19632.

    Article  CAS  PubMed  Google Scholar 

  83. Wagner KJ, Patek CE, Miles C, Christie S, Brookes AJ, Hooper ML . Truncation of WT1 results in downregulation of cyclin G1 and IGFBP-4 expression. Biochem Biophys Res Commun 2001; 287: 977–982.

    Article  CAS  PubMed  Google Scholar 

  84. Englert C, Maheswaran S, Garvin AJ, Kreidberg J, Haber DA . Induction of p21 by the Wilms' tumor suppressor gene WT1. Cancer Res 1997; 57: 1429–1434.

    CAS  PubMed  Google Scholar 

  85. Ryan G, Steele-Perkins V, Morris JF, Rauscher III FJ, Dressler GR . Repression of Pax-2 by WT1 during normal kidney development. Development 1995; 121: 867–875.

    Article  CAS  PubMed  Google Scholar 

  86. Oh S, Song Y, Yim J, Kim TK . The Wilms' tumor 1 tumor suppressor gene represses transcription of the human telomerase reverse transcriptase gene. J Biol Chem 1999; 274: 37473–37478.

    Article  CAS  PubMed  Google Scholar 

  87. Li RS, Law GL, Seifert RA, Romaniuk PJ, Morris DR . Ornithine decarboxylase is a transcriptional target of tumor suppressor WT1. Exp Cell Res 1999; 247: 257–266.

    Article  CAS  PubMed  Google Scholar 

  88. Moshier JA, Skunca M, Wu W, Boppana SM, Rauscher III FJ, Dosescu J . Regulation of ornithine decarboxylase gene expression by the Wilms' tumor suppressor WT1. Nucleic Acids Res 1996; 24: 1149–1157.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Hosono S, Gross I, English MA, Hajra KM, Fearon ER, Licht JD . E-cadherin is a WT1 target gene. J Biol Chem 2000; 275: 10943–10953.

    Article  CAS  PubMed  Google Scholar 

  90. Dejong V, Degeorges A, Filleur S, Ait-Si-Ali S, Mettouchi A, Bornstein P et al. The Wilms' tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun. Oncogene 1999; 18: 3143–3151.

    Article  CAS  PubMed  Google Scholar 

  91. Cook DM, Hinkes MT, Bernfield M, Rauscher III FJ . Transcriptional activation of the syndecan-1 promoter by the Wilms' tumor protein WT1. Oncogene 1996; 13: 1789–1799.

    CAS  PubMed  Google Scholar 

  92. Sim EU, Smith A, Szilagi E, Rae F, Ioannou P, Lindsay MH et al. Wnt-4 regulation by the Wilms' tumour suppressor gene, WT1. Oncogene 2002; 21: 2948–2960.

    Article  CAS  PubMed  Google Scholar 

  93. Dame C, Kirschner KM, Bartz KV, Wallach T, Hussels CS, Scholz H . Wilms tumor suppressor, Wt1, is a transcriptional activator of the erythropoietin gene. Blood 2006; 107: 4282–4290.

    Article  CAS  PubMed  Google Scholar 

  94. Oji Y, Suzuki T, Nakano Y, Maruno M, Nakatsuka S, Jomgeow T et al. Overexpression of the Wilms' tumor gene W T1 in primary astrocytic tumors. Cancer Sci 2004; 95: 822–827.

    Article  CAS  PubMed  Google Scholar 

  95. Ueda T, Oji Y, Naka N, Nakano Y, Takahashi E, Koga S et al. Overexpression of the Wilms' tumor gene WT1 in human bone and soft-tissue sarcomas. Cancer Sci 2003; 94: 271–276.

    Article  CAS  PubMed  Google Scholar 

  96. Nakatsuka S, Oji Y, Horiuchi T, Kanda T, Kitagawa M, Takeuchi T et al. Immunohistochemical detection of WT1 protein in a variety of cancer cells. Mod Pathol 2006; 19: 804–814.

    Article  CAS  PubMed  Google Scholar 

  97. Loeb DM, Evron E, Patel CB, Sharma PM, Niranjan B, Buluwela L et al. Wilms' tumor suppressor gene (WT1) is expressed in primary breast tumors despite tumor-specific promoter methylation. Cancer Res 2001; 61: 921–925.

    CAS  PubMed  Google Scholar 

  98. Oji Y, Yamamoto H, Nomura M, Nakano Y, Ikeba A, Nakatsuka S et al. Overexpression of the Wilms' tumor gene WT1 in colorectal adenocarcinoma. Cancer Sci 2003; 94: 712–717.

    Article  CAS  PubMed  Google Scholar 

  99. Oji Y, Miyoshi S, Maeda H, Hayashi S, Tamaki H, Nakatsuka S et al. Overexpression of the Wilms' tumor gene WT1 in de novo lung cancers. Int J Cancer 2002; 100: 297–303.

    Article  CAS  PubMed  Google Scholar 

  100. Amini Nik S, Hohenstein P, Jadidizadeh A, Van Dam K, Bastidas A, Berry RL et al. Upregulation of Wilms' tumor gene 1 (WT1) in desmoid tumors. Int J Cancer 2005; 114: 202–208.

    Article  CAS  Google Scholar 

  101. Oji Y, Yano M, Nakano Y, Abeno S, Nakatsuka S, Ikeba A et al. Overexpression of the Wilms' tumor gene WT1 in esophageal cancer. Anticancer Res 2004; 24: 3103–3108.

    CAS  PubMed  Google Scholar 

  102. Oji Y, Inohara H, Nakazawa M, Nakano Y, Akahani S, Nakatsuka S et al. Overexpression of the Wilms' tumor gene WT1 in head and neck squamous cell carcinoma. Cancer Sci 2003; 94: 523–529.

    Article  CAS  PubMed  Google Scholar 

  103. Kumar-Singh S, Segers K, Rodeck U, Backhovens H, Bogers J, Weyler J et al. WT1 mutation in malignant mesothelioma and WT1 immunoreactivity in relation to p53 and growth factor receptor expression, cell-type transition, and prognosis. J Pathol 1997; 181: 67–74.

    Article  CAS  PubMed  Google Scholar 

  104. Foster MR, Johnson JE, Olson SJ, Allred DC . Immunohistochemical analysis of nuclear versus cytoplasmic staining of WT1 in malignant mesotheliomas and primary pulmonary adenocarcinomas. Arch Pathol Lab Med 2001; 125: 1316–1320.

    Article  CAS  PubMed  Google Scholar 

  105. Rodeck U, Bossler A, Kari C, Humphreys CW, Gyorfi T, Maurer J et al. Expression of the wt1 Wilms' tumor gene by normal and malignant human melanocytes. Int J Cancer 1994; 59: 78–82.

    Article  CAS  PubMed  Google Scholar 

  106. Dennis SL, Manji SS, Carrington DP, Scarcella DL, Ashley DM, Smith PJ et al. Expression and mutation analysis of the Wilms' tumor 1 gene in human neural tumors. Int J Cancer 2002; 97: 713–715.

    Article  CAS  PubMed  Google Scholar 

  107. Waldstrom M, Grove A . Immunohistochemical expression of wilms tumor gene protein in different histologic subtypes of ovarian carcinomas. Arch Pathol Lab Med 2005; 129: 85–88.

    Article  CAS  PubMed  Google Scholar 

  108. Dupont J, Wang X, Marshall DS, Leitao M, Hedvat CV, Hummer A et al. Wilms Tumor Gene (WT1) and p53 expression in endometrial carcinomas: a study of 130 cases using a tissue microarray. Gynecol Oncol 2004; 94: 449–455.

    Article  CAS  PubMed  Google Scholar 

  109. Hylander B, Repasky E, Shrikant P, Intengan M, Beck A, Driscoll D et al. Expression of Wilms tumor gene (WT1) in epithelial ovarian cancer. Gynecol Oncol 2006; 101: 12–17.

    Article  CAS  PubMed  Google Scholar 

  110. Oji Y, Nakamori S, Fujikawa M, Nakatsuka S, Yokota A, Tatsumi N et al. Overexpression of the Wilms' tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci 2004; 95: 583–587.

    Article  CAS  PubMed  Google Scholar 

  111. Oji Y, Miyoshi Y, Koga S, Nakano Y, Ando A, Nakatsuka S et al. Overexpression of the Wilms' tumor gene WT1 in primary thyroid cancer. Cancer Sci 2003; 94: 606–611.

    Article  CAS  PubMed  Google Scholar 

  112. Campbell CE, Kuriyan NP, Rackley RR, Caulfield MJ, Tubbs R, Finke J et al. Constitutive expression of the Wilms tumor suppressor gene (WT1) in renal cell carcinoma. Int J Cancer 1998; 78: 182–188.

    Article  CAS  PubMed  Google Scholar 

  113. Rong Y, Cheng L, Ning H, Zou J, Zhang Y, Xu F et al. Wilms' tumor 1 and signal transducers and activators of transcription 3 synergistically promote cell proliferation: a possible mechanism in sporadic Wilms' tumor. Cancer Res 2006; 66: 8049–8057.

    Article  CAS  PubMed  Google Scholar 

  114. Carpenter B, Hill KJ, Charalambous M, Wagner KJ, Lahiri D, James DI et al. BASP1 is a transcriptional cosuppressor for the Wilms' tumor suppressor protein WT1. Mol Cell Biol 2004; 24: 537–549.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wang W, Lee SB, Palmer R, Ellisen LW, Haber DA . A functional interaction with CBP contributes to transcriptional activation by the Wilms tumor suppressor WT1. J Biol Chem 2001; 276: 16810–16816.

    Article  CAS  PubMed  Google Scholar 

  116. Maheswaran S, Park S, Bernard A, Morris JF, Rauscher III FJ, Hill DE et al. Physical and functional interaction between WT1 and p53 proteins. Proc Natl Acad Sci USA 1993; 90: 5100–5104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Richard DJ, Schumacher V, Royer-Pokora B, Roberts SG . Par4 is a coactivator for a splice isoform-specific transcriptional activation domain in WT1. Genes Dev 2001; 15: 328–339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Scharnhorst V, Dekker P, van der Eb AJ, Jochemsen AG . Physical interaction between Wilms tumor 1 and p73 proteins modulates their functions. J Biol Chem 2000; 275: 10202–10211.

    Article  CAS  PubMed  Google Scholar 

  119. Lee TH, Lwu S, Kim J, Pelletier J . Inhibition of Wilms tumor 1 transactivation by bone marrow zinc finger 2, a novel transcriptional repressor. J Biol Chem 2002; 277: 44826–44837.

    Article  CAS  PubMed  Google Scholar 

  120. Johnstone RW, Wang J, Tommerup N, Vissing H, Roberts T, Shi Y . Ciao 1 is a novel WD40 protein that interacts with the tumor suppressor protein WT1. J Biol Chem 1998; 273: 10880–10887.

    Article  CAS  PubMed  Google Scholar 

  121. Maheswaran S, Englert C, Zheng G, Lee SB, Wong J, Harkin DP et al. Inhibition of cellular proliferation by the Wilms tumor suppressor WT1 requires association with the inducible chaperone Hsp70. Genes Dev 1998; 12: 1108–1120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Maheswaran S, Englert C, Lee SB, Ezzel RM, Settleman J, Haber DA . E1B 55K sequesters WT1 along with p53 within a cytoplasmic body in adenovirus-transformed kidney cells. Oncogene 1998; 16: 2041–2050.

    Article  CAS  PubMed  Google Scholar 

  123. Wang ZY, Qiu QQ, Seufert W, Taguchi T, Testa JR, Whitmore SA et al. Molecular cloning of the cDNA and chromosome localization of the gene for human ubiquitin-conjugating enzyme 9. J Biol Chem 1996; 271: 24811–24816.

    Article  CAS  PubMed  Google Scholar 

  124. Davies RC, Calvio C, Bratt E, Larsson SH, Lamond AI, Hastie ND . WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes. Genes Dev 1998; 12: 3217–3225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Nachtigal MW, Hirokawa Y, Enyeart-VanHouten DL, Flanagan JN, Hammer GD, Ingraham HA . Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression. Cell 1998; 93: 445–454.

    Article  CAS  PubMed  Google Scholar 

  126. Du X, Hublitz P, Gunther T, Wilhelm D, Englert C, Schule R . The LIM-only coactivator FHL2 modulates WT1 transcriptional activity during gonadal differentiation. Biochim Biophys Acta 2002; 1577: 93–101.

    Article  CAS  PubMed  Google Scholar 

  127. Little NA, Hastie ND, Davies RC . Identification of WTAP, a novel Wilms' tumour 1-associating protein. Hum Mol Genet 2000; 9: 2231–2239.

    Article  CAS  PubMed  Google Scholar 

  128. Moffett P, Bruening W, Nakagama H, Bardeesy N, Housman D, Housman DE et al. Antagonism of WT1 activity by protein self-association. Proc Natl Acad Sci USA 1995; 92: 11105–11109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge Armando Poeppl for critical readings of the manuscript. This work was supported by a grant from the NCI of Canada and the Terry Fox Foundation.

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  1. Department of Cellular and Molecular Biology, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada

    L Yang, Y Han, F Saurez Saiz & M D Minden

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  1. L Yang
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Correspondence to M D Minden.

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Yang, L., Han, Y., Saurez Saiz, F. et al. A tumor suppressor and oncogene: the WT1 story. Leukemia 21, 868–876 (2007). https://doi.org/10.1038/sj.leu.2404624

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