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EMBO J. Aug 15, 1996; 15(16): 4297–4306.
PMCID: PMC452155

PAX8-mediated activation of the wt1 tumor suppressor gene.

Abstract

The developing renal system has long been exploited to study the regulation of gene expression during mesenchymal-epithelial transitions. Several transcription factors, including WT1 and PAX8, are expressed early in nephrogenesis and play a key role in this process. The expression of PAX8 occurs in the induced mesenchyme of the developing kidney prior to the upregulation of WT1 levels in the same cells. In this report, we assessed whether the Pax-8 gene product resides upstream of wt1 in a common regulatory pathway. Transfection studies, as well as gel-shift assays, indicate that PAX8 transactivates wt1 through elements within a 38 bp conserved motif, present in human and murine promoters. Two PAX8 isoforms, generated by alternative splicing at the C-terminus and previously thought to lack transactivation potential, were found to be capable of activating wt1 expression. We also demonstrate that the endogenous wt1 promoter can be upregulated by exogenously supplied PAX8, suggesting that a function of PAX8 during mesenchymal--epithelial cell transition in renal development is to induce wt1 gene expression.

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  • Adams B, Dörfler P, Aguzzi A, Kozmik Z, Urbánek P, Maurer-Fogy I, Busslinger M. Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis. Genes Dev. 1992 Sep;6(9):1589–1607. [PubMed]
  • Auffray C, Rougeon F. Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. Eur J Biochem. 1980 Jun;107(2):303–314. [PubMed]
  • Barberis A, Widenhorn K, Vitelli L, Busslinger M. A novel B-cell lineage-specific transcription factor present at early but not late stages of differentiation. Genes Dev. 1990 May;4(5):849–859. [PubMed]
  • Barr FG, Galili N, Holick J, Biegel JA, Rovera G, Emanuel BS. Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nat Genet. 1993 Feb;3(2):113–117. [PubMed]
  • Beckwith JB, Kiviat NB, Bonadio JF. Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms' tumor. Pediatr Pathol. 1990;10(1-2):1–36. [PubMed]
  • Bopp D, Burri M, Baumgartner S, Frigerio G, Noll M. Conservation of a large protein domain in the segmentation gene paired and in functionally related genes of Drosophila. Cell. 1986 Dec 26;47(6):1033–1040. [PubMed]
  • Bruening W, Pelletier J. A non-AUG translational initiation event generates novel WT1 isoforms. J Biol Chem. 1996 Apr 12;271(15):8646–8654. [PubMed]
  • Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, et al. Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell. 1990 Feb 9;60(3):509–520. [PubMed]
  • Chalepakis G, Fritsch R, Fickenscher H, Deutsch U, Goulding M, Gruss P. The molecular basis of the undulated/Pax-1 mutation. Cell. 1991 Sep 6;66(5):873–884. [PubMed]
  • Coppes MJ, Liefers GJ, Paul P, Yeger H, Williams BR. Homozygous somatic Wt1 point mutations in sporadic unilateral Wilms tumor. Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1416–1419. [PMC free article] [PubMed]
  • Czerny T, Schaffner G, Busslinger M. DNA sequence recognition by Pax proteins: bipartite structure of the paired domain and its binding site. Genes Dev. 1993 Oct;7(10):2048–2061. [PubMed]
  • Dey BR, Sukhatme VP, Roberts AB, Sporn MB, Rauscher FJ, 3rd, Kim SJ. Repression of the transforming growth factor-beta 1 gene by the Wilms' tumor suppressor WT1 gene product. Mol Endocrinol. 1994 May;8(5):595–602. [PubMed]
  • Dressler GR, Douglass EC. Pax-2 is a DNA-binding protein expressed in embryonic kidney and Wilms tumor. Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1179–1183. [PMC free article] [PubMed]
  • Dressler GR, Wilkinson JE, Rothenpieler UW, Patterson LT, Williams-Simons L, Westphal H. Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities. Nature. 1993 Mar 4;362(6415):65–67. [PubMed]
  • Drummond IA, Madden SL, Rohwer-Nutter P, Bell GI, Sukhatme VP, Rauscher FJ., 3rd Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1. Science. 1992 Jul 31;257(5070):674–678. [PubMed]
  • Eccles MR, Yun K, Reeve AE, Fidler AE. Comparative in situ hybridization analysis of PAX2, PAX8, and WT1 gene transcription in human fetal kidney and Wilms' tumors. Am J Pathol. 1995 Jan;146(1):40–45. [PMC free article] [PubMed]
  • Englert C, Hou X, Maheswaran S, Bennett P, Ngwu C, Re GG, Garvin AJ, Rosner MR, Haber DA. WT1 suppresses synthesis of the epidermal growth factor receptor and induces apoptosis. EMBO J. 1995 Oct 2;14(19):4662–4675. [PMC free article] [PubMed]
  • Epstein J, Cai J, Glaser T, Jepeal L, Maas R. Identification of a Pax paired domain recognition sequence and evidence for DNA-dependent conformational changes. J Biol Chem. 1994 Mar 18;269(11):8355–8361. [PubMed]
  • Fraizer GC, Wu YJ, Hewitt SM, Maity T, Ton CC, Huff V, Saunders GF. Transcriptional regulation of the human Wilms' tumor gene (WT1). Cell type-specific enhancer and promiscuous promoter. J Biol Chem. 1994 Mar 25;269(12):8892–8900. [PubMed]
  • Francis-Lang H, Price M, Polycarpou-Schwarz M, Di Lauro R. Cell-type-specific expression of the rat thyroperoxidase promoter indicates common mechanisms for thyroid-specific gene expression. Mol Cell Biol. 1992 Feb;12(2):576–588. [PMC free article] [PubMed]
  • Fridovich-Keil JL, Gudas JM, Bryan IB, Pardee AB. Improved expression vectors for eukaryotic promoter/enhancer studies. Biotechniques. 1991 Nov;11(5):572–579. [PubMed]
  • Glaser T, Walton DS, Maas RL. Genomic structure, evolutionary conservation and aniridia mutations in the human PAX6 gene. Nat Genet. 1992 Nov;2(3):232–239. [PubMed]
  • Gashler AL, Bonthron DT, Madden SL, Rauscher FJ, 3rd, Collins T, Sukhatme VP. Human platelet-derived growth factor A chain is transcriptionally repressed by the Wilms tumor suppressor WT1. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10984–10988. [PMC free article] [PubMed]
  • Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature. 1990 Feb 22;343(6260):774–778. [PubMed]
  • 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 Mar 16;10(6):1125–1129. [PubMed]
  • Gruss P, Walther C. Pax in development. Cell. 1992 May 29;69(5):719–722. [PubMed]
  • 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 U S A. 1991 Nov 1;88(21):9618–9622. [PMC free article] [PubMed]
  • Harrington MA, Konicek B, Song A, Xia XL, Fredericks WJ, Rauscher FJ., 3rd Inhibition of colony-stimulating factor-1 promoter activity by the product of the Wilms' tumor locus. J Biol Chem. 1993 Oct 5;268(28):21271–21275. [PubMed]
  • Hofmann W, Royer HD, Drechsler M, Schneider S, Royer-Pokora B. Characterization of the transcriptional regulatory region of the human WT1 gene. Oncogene. 1993 Nov;8(11):3123–3132. [PubMed]
  • Holst BD, Goomer RS, Wood IC, Edelman GM, Jones FS. Binding and activation of the promoter for the neural cell adhesion molecule by Pax-8. J Biol Chem. 1994 Sep 2;269(35):22245–22252. [PubMed]
  • Kozmik Z, Kurzbauer R, Dörfler P, Busslinger M. Alternative splicing of Pax-8 gene transcripts is developmentally regulated and generates isoforms with different transactivation properties. Mol Cell Biol. 1993 Oct;13(10):6024–6035. [PMC free article] [PubMed]
  • Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D, Jaenisch R. WT-1 is required for early kidney development. Cell. 1993 Aug 27;74(4):679–691. [PubMed]
  • Larsson SH, Charlieu JP, Miyagawa K, Engelkamp D, Rassoulzadegan M, Ross A, Cuzin F, van Heyningen V, Hastie ND. Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing. Cell. 1995 May 5;81(3):391–401. [PubMed]
  • Little MH, Prosser J, Condie A, Smith PJ, Van Heyningen V, Hastie ND. Zinc finger point mutations within the WT1 gene in Wilms tumor patients. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4791–4795. [PMC free article] [PubMed]
  • Maulbecker CC, Gruss P. The oncogenic potential of Pax genes. EMBO J. 1993 Jun;12(6):2361–2367. [PMC free article] [PubMed]
  • 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 Oct 6;270(40):23785–23789. [PubMed]
  • Mundlos S, Pelletier J, Darveau A, Bachmann M, Winterpacht A, Zabel B. Nuclear localization of the protein encoded by the Wilms' tumor gene WT1 in embryonic and adult tissues. Development. 1993 Dec;119(4):1329–1341. [PubMed]
  • Park S, Bernard A, Bove KE, Sens DA, Hazen-Martin DJ, Garvin AJ, Haber DA. Inactivation of WT1 in nephrogenic rests, genetic precursors to Wilms' tumour. Nat Genet. 1993 Dec;5(4):363–367. [PubMed]
  • Patterson LT, Dressler GR. The regulation of kidney development: new insights from an old model. Curr Opin Genet Dev. 1994 Oct;4(5):696–702. [PubMed]
  • Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, et al. Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell. 1991 Oct 18;67(2):437–447. [PubMed]
  • Pelletier J, Schalling M, Buckler AJ, Rogers A, Haber DA, Housman D. Expression of the Wilms' tumor gene WT1 in the murine urogenital system. Genes Dev. 1991 Aug;5(8):1345–1356. [PubMed]
  • Plachov D, Chowdhury K, Walther C, Simon D, Guenet JL, Gruss P. Pax8, a murine paired box gene expressed in the developing excretory system and thyroid gland. Development. 1990 Oct;110(2):643–651. [PubMed]
  • Poleev A, Fickenscher H, Mundlos S, Winterpacht A, Zabel B, Fidler A, Gruss P, Plachov D. PAX8, a human paired box gene: isolation and expression in developing thyroid, kidney and Wilms' tumors. Development. 1992 Nov;116(3):611–623. [PubMed]
  • Poleev A, Wendler F, Fickenscher H, Zannini MS, Yaginuma K, Abbott C, Plachov D. Distinct functional properties of three human paired-box-protein, PAX8, isoforms generated by alternative splicing in thyroid, kidney and Wilms' tumors. Eur J Biochem. 1995 Mar 15;228(3):899–911. [PubMed]
  • Pritchard-Jones K, Fleming S, Davidson D, Bickmore W, Porteous D, Gosden C, Bard J, Buckler A, Pelletier J, Housman D, et al. The candidate Wilms' tumour gene is involved in genitourinary development. Nature. 1990 Jul 12;346(6280):194–197. [PubMed]
  • Rauscher FJ., 3rd The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. FASEB J. 1993 Jul;7(10):896–903. [PubMed]
  • Rauscher FJ, 3rd, Morris JF, Tournay OE, Cook DM, Curran T. Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence. Science. 1990 Nov 30;250(4985):1259–1262. [PubMed]
  • Rupprecht HD, Drummond IA, Madden SL, Rauscher FJ, 3rd, Sukhatme VP. The Wilms' tumor suppressor gene WT1 is negatively autoregulated. J Biol Chem. 1994 Feb 25;269(8):6198–6206. [PubMed]
  • Ryan G, Steele-Perkins V, Morris JF, Rauscher FJ, 3rd, Dressler GR. Repression of Pax-2 by WT1 during normal kidney development. Development. 1995 Mar;121(3):867–875. [PubMed]
  • Shapiro DN, Sublett JE, Li B, Downing JR, Naeve CW. Fusion of PAX3 to a member of the forkhead family of transcription factors in human alveolar rhabdomyosarcoma. Cancer Res. 1993 Nov 1;53(21):5108–5112. [PubMed]
  • Stuart ET, Haffner R, Oren M, Gruss P. Loss of p53 function through PAX-mediated transcriptional repression. EMBO J. 1995 Nov 15;14(22):5638–5645. [PMC free article] [PubMed]
  • Tagge EP, Hanson P, Re GG, Othersen HB, Jr, Smith CD, Garvin AJ. Paired box gene expression in Wilms' tumor. J Pediatr Surg. 1994 Feb;29(2):134–141. [PubMed]
  • Varanasi R, Bardeesy N, Ghahremani M, Petruzzi MJ, Nowak N, Adam MA, Grundy P, Shows TB, Pelletier J. Fine structure analysis of the WT1 gene in sporadic Wilms tumors. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3554–3558. [PMC free article] [PubMed]
  • Wang ZY, Madden SL, Deuel TF, Rauscher FJ., 3rd The Wilms' tumor gene product, WT1, represses transcription of the platelet-derived growth factor A-chain gene. J Biol Chem. 1992 Nov 5;267(31):21999–22002. [PubMed]
  • Wang ZY, Qiu QQ, Gurrieri M, Huang J, Deuel TF. WT1, the Wilms' tumor suppressor gene product, represses transcription through an interactive nuclear protein. Oncogene. 1995 Mar 16;10(6):1243–1247. [PubMed]
  • Weitzman JB, Pasqualini R, Takada Y, Hemler ME. The function and distinctive regulation of the integrin VLA-3 in cell adhesion, spreading, and homotypic cell aggregation. J Biol Chem. 1993 Apr 25;268(12):8651–8657. [PubMed]
  • Werner H, Re GG, Drummond IA, Sukhatme VP, Rauscher FJ, 3rd, Sens DA, Garvin AJ, LeRoith D, Roberts CT., Jr 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 U S A. 1993 Jun 15;90(12):5828–5832. [PMC free article] [PubMed]
  • Wu Y, Fraizer GC, Saunders GF. GATA-1 transactivates the WT1 hematopoietic specific enhancer. J Biol Chem. 1995 Mar 17;270(11):5944–5949. [PubMed]
  • Zannini M, Francis-Lang H, Plachov D, Di Lauro R. Pax-8, a paired domain-containing protein, binds to a sequence overlapping the recognition site of a homeodomain and activates transcription from two thyroid-specific promoters. Mol Cell Biol. 1992 Sep;12(9):4230–4241. [PMC free article] [PubMed]

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