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hnRNP-U directly interacts with WT1 and modulates WT1 transcriptional activation

Oncogene volume 26, pages 1484–1491 (2007)Cite this article

Abstract

The Wilms' tumour suppressor gene, WT1, encodes a zinc-finger protein that is mutated in Wilms' tumours and highly expressed in a wide variety of other malignancies. WT1 is a transcription factor that is likely to have additional, post-transcriptional, regulatory roles, although the molecular mechanisms by which WT1 acts remain poorly understood. We have combined genetic and biochemical approaches to show, that endogenous WT1 binds to heterogeneous nuclear ribonuclear protein U (hnRNP-U), that this interaction does not require any other proteins or nucleic acids, involves the zinc-fingers of WT1 and the middle domain of hnRNP-U, and that hnRNP-U can modulate WT1 transcriptional activation of a bona fide WT1 target gene. These findings increase our knowledge of how WT1 exerts its transcriptional regulatory role and suggests that hnRNP-U may be a candidate Wilms' tumour gene at 1q44.

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References

  • Armstrong JF, Pritchard-Jones K, Bickmore WA, Hastie ND, Bard JB . (1993). The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo. Mech Dev 40: 85–97.

    Article  CAS  Google Scholar 

  • Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F et al. (1997). Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17: 467–470.

    Article  CAS  Google Scholar 

  • Bergmann L, Maurer U, Weidmann E . (1997). Wilms' tumor gene expression in acute myeloid leukemias. Leuk Lymphoma 25: 435–443.

    Article  CAS  Google Scholar 

  • Breslow N, Beckwith JB, Ciol M, Sharples K . (1988). Age distribution of Wilms' tumor: report from the National Wilms' Tumor Study. Cancer Res 48: 1653–1657.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Caricasole A, Duarte A, Larsson SH, Hastie ND, Little M, Holmes G et al. (1996). RNA binding by the Wilms tumor suppressor zinc finger proteins. Proc Natl Acad Sci USA 93: 7562–7566.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Challen G, Gardiner B, Caruana G, Kostoulias X, Martinez G, Crowe M et al. (2005). Temporal and spatial transcriptional programs in murine kidney development. Physiol Genomics 23: 159–171.

    Article  CAS  Google Scholar 

  • 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: 3217–3225.

    Article  CAS  Google Scholar 

  • 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: 774–778.

    Article  CAS  Google Scholar 

  • Hammes A, Guo JK, Lutsch G, Leheste JR, Landrock D, Ziegler U et al. (2001). Two splice variants of the Wilms' tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106: 319–329.

    Article  CAS  Google Scholar 

  • Hastie ND . (1994). The genetics of Wilms' tumor – a case of disrupted development. Annu Rev Genet 28: 523–558.

    Article  CAS  Google Scholar 

  • Heilbronn R, Engstler M, Weger S, Krahn A, Schetter C, Boshart S . (2003). ssDNA-dependent colocalization of adeno-associated virus Rep and herpes simplex virus ICP8 in nuclear replication domains. Nucleic Acid Res 31: 6206–6213.

    Article  CAS  Google Scholar 

  • Kanai Y, Dohmae N, Hirokawa N . (2004). Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron 43: 513–525.

    Article  CAS  Google Scholar 

  • Kiledjian M, Dreyfuss G . (1992). Primary structure and binding activity of the hnRNP U protein: binding RNA through RGG box. EMBO J 11: 2655–2664.

    Article  CAS  Google Scholar 

  • Kim MK, Nikodem VM . (1999). hnRNP U inhibits carboxy-terminal domain phosphorylation by TFIIH and represses RNA polymerase II elongation. Mol Cell Biol 19: 6833–6844.

    Article  CAS  Google Scholar 

  • Krecic AM, Swanson MS . (1999). hnRNP complexes: composition, structure, and function. Curr Opin Cell Biol 11: 363–371.

    Article  CAS  Google Scholar 

  • Kukalev A, Nord Y, Palmberg C, Bergman T, Percipalle P . (2005). Actin and hnRNP U cooperate for productive transcription by RNA polymerase II. Nat Struct Mol Biol 12: 238–244.

    Article  CAS  Google Scholar 

  • Ladomery MR, Slight J, Mc Ghee S, Hastie ND . (1999). Presence of WT1, the Wilm's tumor suppressor gene product, in nuclear poly(A)(+) ribonucleoprotein. J Biol Chem 274: 36520–36526.

    Article  CAS  Google Scholar 

  • Larsson SH, Charlieu JP, Miyagawa K, Engelkamp D, Rassoulzadegan M, Ross A et al. (1995). Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing. Cell 81: 391–401.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Little M, Holmes G, Walsh P . (1999). WT1: what has the last decade told us? BioEssays 21: 191–202.

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Miles CG, Slight J, Spraggon L, O'Sullivan M, Patek C, Hastie ND . (2003). Mice lacking the 68-amino-acid, mammal-specific N-terminal extension of WT1 develop normally and are fertile. Mol Cell Biol 23: 2608–2613.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Natoli TA, McDonald A, Alberta JA, Taglienti ME, Housman DE, Kreidberg JA . (2002). A mammal-specific exon of WT1 is not required for development or fertility. Mol Cell Biol 22: 4433–4438.

    Article  CAS  Google Scholar 

  • Niksic M, Slight J, Sanford JR, Caceres JF, Hastie ND . (2004). The Wilms' tumour protein (WT1) shuttles between nucleus and cytoplasm and is present in functional polysomes. Hum Mol Genet 13: 463–471.

    Article  CAS  Google Scholar 

  • Oji Y, Miyoshi S, Takahashi E, Koga S, Nakano Y, Shintani Y et al. (2004). Absence of mutations in the Wilms' tumor gene wt1 in de novo non-small cell lung cancers. Neoplasma 51: 17–20.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Pinol-Roma S, Choi YD, Matunis MJ, Dreyfuss G . (1988). Immunopurification of heterogeneous nuclear ribonucleoprotein particles reveals an assortment of RNA-binding proteins. Genes Dev 2: 215–227.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Roberts SG . (2005). Transcriptional regulation by WT1 in development. Curr Opin Genet Dev 15: 542–547.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Romig H, Fackelmayer FO, Renz A, Ramsperger U, Richter A . (1992). Characterization of SAF-A, a novel nuclear DNA binding protein from HeLa cells with high affinity for nuclear matrix/scaffold attachment DNA elements. EMBO J 11: 3431–3440.

    Article  CAS  Google Scholar 

  • Scharnhorst V, Kranenburg O, van der Eb AJ, Jochemsen AG . (1997). Differential regulation of the Wilms' tumor gene, WT1, during differentiation of embryonal carcinoma and embryonic stem cells. Cell Growth Differ 8: 133–143.

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  • Wagner N, Wagner KD, Theres H, Englert C, Schedl A, Scholz H . (2005). Coronary vessel development requires activation of the TrkB neurotrophin receptor by the Wilms' tumor transcription factor Wt1. Genes Dev 19: 2631–2642.

    Article  CAS  Google Scholar 

  • Wagner N, Wagner KD, Xing Y, Scholz H, Schedl A . (2004). The major podocyte protein nephrin is transcriptionally activated by the Wilms' tumor suppressor WT1. J Am Soc Nephrol 15: 3044–3051.

    Article  Google Scholar 

  • Wilhelm D., Englert C . (2002). The Wilms' tumor suppressor WT1 regulates early gonad development by activation of Sf1. Genes Dev 16: 1839–1851.

    Article  CAS  Google Scholar 

  • Williams RD, Hing SN, Greer BT, Whiteford CC, Wei JS, Natrajan R et al. (2004). Prognostic classification of relapsing favorable histology Wilms tumor using cDNA microarray expression profiling and support vector machines. Genes Chromosomes Cancer 41: 65–79.

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Zapata-Benavides P, Tuna M, Lopez-Berestein G, Tari AM . (2002). Downregulation of Wilms' tumor 1 protein inhibits breast cancer proliferation. Biochem Biophys Res Commun 295: 784–790.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Ms Kippi Rai-Spraggon for helpful insights and preparation of this manuscript and Dr Cathy Mendelsohn for critical reading of this manuscript; also Ms Katie Browne for excellent editorial assistance and Mr Douglas Stuart for help with the figures. We also thank Dr Dominic Campopiano and Dr Nick Tomczyk for technical assistance, Dr Jordan Kreidberg, Dr Klaus Rajewsky, Dr Vera Nikodem, Dr Myung Kim, Dr Gideon Dreyfuss and Dr Julia Dorin for reagents.

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Author notes

  1. L Spraggon and T Dudnakova: These two authors are joint first authors.

Authors and Affiliations

  1. MRC Human Genetics Unit, Western General Hospital, Crew Road, Edinburgh, UK

    L Spraggon, T Dudnakova, J Slight, O Lustig-Yariv, J Cotterell & N Hastie

  2. Institute of Human Genetics, International Centre for Life, University of Newcastle, Central Parkway, Newcastle, UK

    C Miles

  3. College of Physicians and Surgeons, Columbia University, New York, NY, USA

    L Spraggon

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  1. L Spraggon
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Correspondence to N Hastie.

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Spraggon, L., Dudnakova, T., Slight, J. et al. hnRNP-U directly interacts with WT1 and modulates WT1 transcriptional activation. Oncogene 26, 1484–1491 (2007). https://doi.org/10.1038/sj.onc.1209922

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