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. 1996 Mar 15;24(6):1149–1157. doi: 10.1093/nar/24.6.1149

Regulation of ornithine decarboxylase gene expression by the Wilms' tumor suppressor WT1.

J A Moshier 1, M Skunca 1, W Wu 1, S M Boppana 1, F J Rauscher 3rd 1, J Dosescu 1
PMCID: PMC145756  PMID: 8604351

Abstract

The importance of ornithine decarboxylase (ODC) to cell proliferation is underscored by the complex array of cell-specific mechanisms invoked to regulate its synthesis and activity. Misregulation of ODC has severe negative consequences on normal cell function, including the acquisition of tumorigenic growth properties by cells overexpressing ODC. We hypothesize that ODC gene expression is a candidate target for the anti-proliferative function of certain tumor suppressors. Here we show that the Wilms' tumor suppressor WT1 binds to multiple sites within the human ODC promoter, as determined by DNase I protection and methylation interference assays. The expression of WT1 in transfected HCT 116, NIH/3T3 and HepG2 cells represses activity of the ODC promoter controlling expression of a luciferase reporter gene. In contrast WT1 expression enhances ODC promoter activity in SV40-transfected HepG2 cells. Both the extent of modulation of ODC gene expression and the mediating WT1 binding elements are cell specific. Constructs expressing WT1 deletion mutants implicate two regions required for repressor function, as well as an intrinsic activation domain. Understanding the regulation of ODC gene expression by WT1 may provide valuable insights into the roles of both WT1 and ODC in development and tumorigenesis.

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Selected References

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  1. Abrahamsen M. S., Morris D. R. Cell type-specific mechanisms of regulating expression of the ornithine decarboxylase gene after growth stimulation. Mol Cell Biol. 1990 Oct;10(10):5525–5528. doi: 10.1128/mcb.10.10.5525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Aden D. P., Fogel A., Plotkin S., Damjanov I., Knowles B. B. Controlled synthesis of HBsAg in a differentiated human liver carcinoma-derived cell line. Nature. 1979 Dec 6;282(5739):615–616. doi: 10.1038/282615a0. [DOI] [PubMed] [Google Scholar]
  3. Auvinen M., Paasinen A., Andersson L. C., Hölttä E. Ornithine decarboxylase activity is critical for cell transformation. Nature. 1992 Nov 26;360(6402):355–358. doi: 10.1038/360355a0. [DOI] [PubMed] [Google Scholar]
  4. Call K. M., Glaser T., Ito C. Y., Buckler A. J., Pelletier J., Haber D. A., Rose E. A., Kral A., Yeger H., Lewis W. H. 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. doi: 10.1016/0092-8674(90)90601-a. [DOI] [PubMed] [Google Scholar]
  5. Coppes M. J., Campbell C. E., Williams B. R. The role of WT1 in Wilms tumorigenesis. FASEB J. 1993 Jul;7(10):886–895. doi: 10.1096/fasebj.7.10.8393819. [DOI] [PubMed] [Google Scholar]
  6. Drummond I. A., Madden S. L., Rohwer-Nutter P., Bell G. I., Sukhatme V. P., Rauscher F. J., 3rd Repression of the insulin-like growth factor II gene by the Wilms tumor suppressor WT1. Science. 1992 Jul 31;257(5070):674–678. doi: 10.1126/science.1323141. [DOI] [PubMed] [Google Scholar]
  7. Gessler M., Poustka A., Cavenee W., Neve R. L., Orkin S. H., Bruns G. A. Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature. 1990 Feb 22;343(6260):774–778. doi: 10.1038/343774a0. [DOI] [PubMed] [Google Scholar]
  8. Ghoda L., Sidney D., Macrae M., Coffino P. Structural elements of ornithine decarboxylase required for intracellular degradation and polyamine-dependent regulation. Mol Cell Biol. 1992 May;12(5):2178–2185. doi: 10.1128/mcb.12.5.2178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Grens A., Scheffler I. E. The 5'- and 3'-untranslated regions of ornithine decarboxylase mRNA affect the translational efficiency. J Biol Chem. 1990 Jul 15;265(20):11810–11816. [PubMed] [Google Scholar]
  10. Hagen G., Müller S., Beato M., Suske G. Cloning by recognition site screening of two novel GT box binding proteins: a family of Sp1 related genes. Nucleic Acids Res. 1992 Nov 11;20(21):5519–5525. doi: 10.1093/nar/20.21.5519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Halmekytö M., Alhonen L., Wahlfors J., Sinervirta R., Jänne O. A., Jänne J. Position-independent, aberrant expression of the human ornithine decarboxylase gene in transgenic mice. Biochem Biophys Res Commun. 1991 Oct 15;180(1):262–267. doi: 10.1016/s0006-291x(05)81286-0. [DOI] [PubMed] [Google Scholar]
  12. Harrington M. A., Konicek B., Song A., Xia X. L., Fredericks W. J., Rauscher F. J., 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] [Google Scholar]
  13. Heby O., Persson L. Molecular genetics of polyamine synthesis in eukaryotic cells. Trends Biochem Sci. 1990 Apr;15(4):153–158. doi: 10.1016/0968-0004(90)90216-x. [DOI] [PubMed] [Google Scholar]
  14. Hewitt S. M., Hamada S., McDonnell T. J., Rauscher F. J., 3rd, Saunders G. F. Regulation of the proto-oncogenes bcl-2 and c-myc by the Wilms' tumor suppressor gene WT1. Cancer Res. 1995 Nov 15;55(22):5386–5389. [PubMed] [Google Scholar]
  15. Katz A., Kahana C. Transcriptional activation of mammalian ornithine decarboxylase during stimulated growth. Mol Cell Biol. 1987 Jul;7(7):2641–2643. doi: 10.1128/mcb.7.7.2641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Li R. S., Abrahamsen M. S., Johnson R. R., Morris D. R. Complex interactions at a GC-rich domain regulate cell type-dependent activity of the ornithine decarboxylase promoter. J Biol Chem. 1994 Mar 18;269(11):7941–7949. [PubMed] [Google Scholar]
  17. Madden S. L., Cook D. M., Morris J. F., Gashler A., Sukhatme V. P., Rauscher F. J., 3rd Transcriptional repression mediated by the WT1 Wilms tumor gene product. Science. 1991 Sep 27;253(5027):1550–1553. doi: 10.1126/science.1654597. [DOI] [PubMed] [Google Scholar]
  18. Madden S. L., Rauscher F. J., 3rd Positive and negative regulation of transcription and cell growth mediated by the EGR family of zinc-finger gene products. Ann N Y Acad Sci. 1993 Jun 11;684:75–84. doi: 10.1111/j.1749-6632.1993.tb32272.x. [DOI] [PubMed] [Google Scholar]
  19. Maheswaran S., Park S., Bernard A., Morris J. F., Rauscher F. J., 3rd, Hill D. E., Haber D. A. Physical and functional interaction between WT1 and p53 proteins. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5100–5104. doi: 10.1073/pnas.90.11.5100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Morris J. F., Madden S. L., Tournay O. E., Cook D. M., Sukhatme V. P., Rauscher F. J., 3rd Characterization of the zinc finger protein encoded by the WT1 Wilms' tumor locus. Oncogene. 1991 Dec;6(12):2339–2348. [PubMed] [Google Scholar]
  21. Moshier J. A., Dosescu J., Skunca M., Luk G. D. Transformation of NIH/3T3 cells by ornithine decarboxylase overexpression. Cancer Res. 1993 Jun 1;53(11):2618–2622. [PubMed] [Google Scholar]
  22. Moshier J. A., Gilbert J. D., Skunca M., Dosescu J., Almodovar K. M., Luk G. D. Isolation and expression of a human ornithine decarboxylase gene. J Biol Chem. 1990 Mar 25;265(9):4884–4892. [PubMed] [Google Scholar]
  23. Moshier J. A., Malecka-Panas E., Geng H., Dosescu J., Tureaud J., Skunca M., Majumdar A. P. Ornithine decarboxylase transformation of NIH/3T3 cells is mediated by altered epidermal growth factor receptor activity. Cancer Res. 1995 Nov 15;55(22):5358–5365. [PubMed] [Google Scholar]
  24. Moshier J. A., Osborne D. L., Skunca M., Dosescu J., Gilbert J. D., Fitzgerald M. C., Polidori G., Wagner R. L., Friezner Degen S. J., Luk G. D. Multiple promoter elements govern expression of the human ornithine decarboxylase gene in colon carcinoma cells. Nucleic Acids Res. 1992 May 25;20(10):2581–2590. doi: 10.1093/nar/20.10.2581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Olson E. N., Spizz G. Mitogens and protein synthesis inhibitors induce ornithine decarboxylase gene transcription through separate mechanisms in the BC3H1 muscle cell line. Mol Cell Biol. 1986 Aug;6(8):2792–2799. doi: 10.1128/mcb.6.8.2792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Palvimo J. J., Eisenberg L. M., Jänne O. A. Protein-DNA interactions in the cAMP responsive promoter region of the murine ornithine decarboxylase gene. Nucleic Acids Res. 1991 Jul 25;19(14):3921–3927. doi: 10.1093/nar/19.14.3921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pegg A. E. Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. 1988 Feb 15;48(4):759–774. [PubMed] [Google Scholar]
  28. Pritchard-Jones K., Fleming S., Davidson D., Bickmore W., Porteous D., Gosden C., Bard J., Buckler A., Pelletier J., Housman D. The candidate Wilms' tumour gene is involved in genitourinary development. Nature. 1990 Jul 12;346(6280):194–197. doi: 10.1038/346194a0. [DOI] [PubMed] [Google Scholar]
  29. Pritchard-Jones K., Hastie N. D. Wilms' tumour as a paradigm for the relationship of cancer to development. Cancer Surv. 1990;9(3):555–578. [PubMed] [Google Scholar]
  30. Rauscher F. J., 3rd, Morris J. F., Tournay O. E., Cook D. M., 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. doi: 10.1126/science.2244209. [DOI] [PubMed] [Google Scholar]
  31. Rauscher F. J., 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] [Google Scholar]
  32. Rosenthal N. Identification of regulatory elements of cloned genes with functional assays. Methods Enzymol. 1987;152:704–720. doi: 10.1016/0076-6879(87)52075-4. [DOI] [PubMed] [Google Scholar]
  33. Saffer J. D., Jackson S. P., Thurston S. J. SV40 stimulates expression of the transacting factor Sp1 at the mRNA level. Genes Dev. 1990 Apr;4(4):659–666. doi: 10.1101/gad.4.4.659. [DOI] [PubMed] [Google Scholar]
  34. Sarfati P., Seva C., Scemama J. L., Pradayrol L., Vaysse N. Effect of basic fibroblast growth factor on ornithine decarboxylase activity and mRNA expression in a pancreatic tumoral cell line (AR4-2J). Pancreas. 1992;7(6):657–663. doi: 10.1097/00006676-199211000-00006. [DOI] [PubMed] [Google Scholar]
  35. Scalabrino G., Ferioli M. E. Polyamines in mammalian tumors. Part I. Adv Cancer Res. 1981;35:151–268. doi: 10.1016/s0065-230x(08)60911-2. [DOI] [PubMed] [Google Scholar]
  36. Scalabrino G., Ferioli M. E. Polyamines in mammalian tumors. Part II. Adv Cancer Res. 1982;36:1–102. doi: 10.1016/s0065-230x(08)60422-4. [DOI] [PubMed] [Google Scholar]
  37. Steglich C., Scheffler I. E. An ornithine decarboxylase-deficient mutant of Chinese hamster ovary cells. J Biol Chem. 1982 Apr 25;257(8):4603–4609. [PubMed] [Google Scholar]
  38. Wang Z. Y., Madden S. L., Deuel T. F., Rauscher F. J., 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] [Google Scholar]
  39. Wang Z. Y., Qiu Q. Q., Deuel T. F. The Wilms' tumor gene product WT1 activates or suppresses transcription through separate functional domains. J Biol Chem. 1993 May 5;268(13):9172–9175. [PubMed] [Google Scholar]
  40. Zhai W. R., Vajta G., Acs G., Paronetto F. A nude mouse model for the in vivo production of hepatitis B virus. Gastroenterology. 1990 Feb;98(2):470–477. doi: 10.1016/0016-5085(90)90840-w. [DOI] [PubMed] [Google Scholar]
  41. Zheng S. A., McElwain C. M., Taffet S. M. Regulation of mouse ornithine decarboxylase gene expression in a macrophage-like cell line: synergistic induction by bacterial lipopolysaccharide and cAMP. Biochem Biophys Res Commun. 1991 Feb 28;175(1):48–54. doi: 10.1016/s0006-291x(05)81198-2. [DOI] [PubMed] [Google Scholar]

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