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Transcriptional activation of c-myc proto-oncogene by WT1 protein

Oncogene volume 23, pages 6933–6941 (2004)Cite this article

Abstract

The Wilms’ tumor 1 gene (WT1) plays an essential role in urogenital development and malignancy. Through DNA binding, WT1 can either enhance or repress transcription depending on the context of the DNA-binding sites or the cell type in which it is expressed. WT1 is overexpressed in a variety of human cancers, including leukemia and breast cancer; in these diseases, the expression of WT1 is associated with a poor prognosis. To determine how WT1 affects c-myc expression in the context of breast cancer cells, we have examined the ability of both endogenous and exogenous WT1 proteins in breast cancer cells to bind to the c-myc promoter in vivo. Using c-myc-promoter-driven luciferase constructs, we found that different forms of WT1 could enhance the expression of the reporter. Unlike other studies where WT1 is reported to be a negative regulator of c-myc, we found that both the − and + KTS forms of WT1 could act to enhance c-myc expression, depending on the cell type. The WT1-binding site near the second major transcription start site of the c-myc promoter was confirmed to be involved in upregulation of human c-myc by WT1. Finally, we demonstrated that overexpression of WT1 induced a significant increase in the abundance of endogenous c-myc protein in breast cancer cells, consistent with the upregulation of c-myc transcription following WT1 induction. These observations strongly argue that in the case of breast cancer WT1 is functioning as an oncogene in part by stimulating the expression of c-myc.

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References

  • Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, Palmiter RD and Brinster RL . (1985). Nature, 318, 533–538.

  • Algar EM, Khromykh T, Smith SI, Blackburn DM, Bryson GJ and Smith PJ . (1996). Oncogene, 12, 1005–1014.

  • Bruening W, Gros P, Sato T, Stanimir J, Nakamura Y, Housman D and Pelletier J . (1993). Cancer Invest., 11, 393–399.

  • Daksis JI, Lu RY, Facchini LM, Marhin WW and Penn LJ . (1994). Oncogene, 9, 3635–3645.

  • Ellisen LW, Carlesso N, Cheng T, Scadden DT and Haber DA . (2001). EMBO J., 20, 1897–1909.

  • Englert C, Maheswaran S, Garvin AJ, Kreidberg J and Haber DA . (1997). Cancer Res., 57, 1429–1434.

  • Evan GI, Wyllie AH, Gilbert CS, Littlewood TD, Land H, Brooks M, Waters CM, Penn LZ and Hancock DC . (1992). Cell, 69, 119–128.

  • Haber DA and Buckler AJ . (1992). New Biol., 4, 97–106.

  • Haber DA, Buckler AJ, Glaser T, Call KM, Pelletier J, Sohn RL, Douglass EC and Housman DE . (1990). Cell, 61, 1257–1269.

  • Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM and Housman DE . (1991). Proc. Natl. Acad. Sci. USA, 88, 9618–9622.

  • Heckman C, Mochon E, Arcinas M and Boxer LM . (1997). J. Biol. Chem., 272, 19609–19614.

  • Herzer U, Crocoll A, Barton D, Howells N and Englert C . (1999). Curr. Biol., 9, 837–840.

  • Hewitt SM, Hamada S, McDonnell TJ, Rauscher III FJ and Saunders GF . (1995). Cancer Res., 55, 5386–5389.

  • Kreidberg JA . (1996). Med. Pediatr. Oncol., 27, 445–452.

  • Lee SB and Haber DA . (2001). Exp. Cell Res., 264, 74–99.

  • Lee TH and Pelletier J . (2001). Physiol. Genomics, 7, 187–200.

  • Li RS, Law GL, Seifert RA, Romaniuk PJ and Morris DR . (1999). Exp. Cell Res., 247, 257–266.

  • Loeb DM, Evron E, Patel CB, Sharma PM, Niranjan B, Buluwela L, Weitzman SA, Korz D and Sukumar S . (2001). Cancer Res., 61, 921–925.

  • Loeb DM, Korz D, Katsnelson M, Burwell EA, Friedman AD and Sukumar S . (2002). J. Biol. Chem., 277, 19627–19632.

  • Madden SL, Cook DM and Rauscher III FJ . (1993). Oncogene, 8, 1713–1720.

  • Mayo MW, Wang CY, Drouin SS, Madrid LV, Marshall AF, Reed JC, Weissman BE and Baldwin AS . (1999). EMBO J., 18, 3990–4003.

  • Menssen HD, Bertelmann E, Bartelt S, Schmidt RA, Pecher G, Schramm K and Thiel E . (2000). J. Cancer Res. Clin. Oncol., 126, 226–232.

  • Miyoshi Y, Ando A, Egawa C, Taguchi T, Tamaki Y, Tamaki H, Sugiyama H and Noguchi S . (2002). Clin. Cancer Res., 8, 1167–1171.

  • Nakagama H, Heinrich G, Pelletier J and Housman DE . (1995). Mol. Cell. Biol., 15, 1489–1498.

  • Nisen PD, Zimmerman KA, Cotter SV, Gilbert F and Alt FW . (1986). Cancer Res., 46, 6217–6222.

  • Oh S, Song Y, Yim J and Kim TK . (1999). J. Biol. Chem., 274, 37473–37478.

  • Park S, Bernard A, Bove KE, Sens DA, Hazen-Martin DJ, Garvin AJ and Haber DA . (1993a). Nat. Genet., 5, 363–367.

  • Park S, Schalling M, Bernard A, Maheswaran S, Shipley GC, Roberts D, Fletcher J, Shipman R, Rheinwald J and Demetri G . (1993b). Nat. Genet., 4, 415–420.

  • Pelletier J, Bruening W, Li FP, Haber DA, Glaser T and Housman DE . (1991a). Nature, 353, 431–434.

  • Pelletier J, Schalling M, Buckler AJ, Rogers A, Haber DA and Housman D . (1991b). Genes Dev., 5, 1345–1356.

  • Pritchard-Jones K and Fleming S . (1991). Oncogene, 6, 2211–2220.

  • Rackley RR, Flenniken AM, Kuriyan NP, Kessler PM, Stoler MH and Williams BR . (1993). Cell Growth Differ., 4, 1023–1031.

  • Rauscher III FJ . (1993). Adv. Exp. Med. Biol., 348, 23–29.

  • Reddy JC and Licht JD . (1996). Biochim. Biophys. Acta, 1287, 1–28.

  • Scharnhorst V, van der Eb AJ and Jochemsen AG . (2001). Gene, 273, 141–161.

  • Silberstein GB, Van Horn K, Strickland P, Roberts Jr CT and Daniel CW . (1997). Proc. Natl. Acad. Sci. USA, 94, 8132–8137.

  • Svedberg H, Chylicki K, Baldetorp B, Rauscher III FJ and Gullberg U . (1998). Oncogene, 16, 925–932.

  • Svedberg H, Richter J and Gullberg U . (2001). Leukemia, 15, 1914–1922.

  • Taub R, Moulding C, Battey J, Murphy W, Vasicek T, Lenoir GM and Leder P . (1984). Cell, 36, 339–348.

  • Telerman A, Dodemont H, Degraef C, Galand P, Bauwens S, Van Oostveldt P and Amson RB . (1992). Oncogene, 7, 2545–2548.

  • Udtha M, Lee SJ, Alam R, Coombes K and Huff V . (2003). Oncogene, 22, 3821–3826.

  • Wang ZY, Qiu QQ, Enger KT and Deuel TF . (1993). Proc. Natl. Acad. Sci. USA, 90, 8896–8900.

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Acknowledgements

We thank Dr Linda Penn for providing the luciferase plasmids and Dr Sam Benchimol for a critical review. This research was supported by the Ontario Cancer Institute, the National Cancer Institute of Canada Terry Fox New Initiative Program and the Canadian Breast Cancer Research Initiative.

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  1. Department of Cellular and Molecular Biology, Ontario Cancer Institute, University Health Network, Toronto, M5G 2M9, Ontario, Canada

    Youqi Han, Serban San-Marina, Jian Liu & Mark D Minden

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  1. Youqi Han
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Correspondence to Mark D Minden.

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Han, Y., San-Marina, S., Liu, J. et al. Transcriptional activation of c-myc proto-oncogene by WT1 protein. Oncogene 23, 6933–6941 (2004). https://doi.org/10.1038/sj.onc.1207609

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