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Antiapoptotic function of 17AA(+)WT1 (Wilms' tumor gene) isoforms on the intrinsic apoptosis pathway

Abstract

The WT1 gene is overexpressed in human primary leukemia and a wide variety of solid cancers. The WT1 gene is alternatively spliced at two sites, yielding four isoforms: 17AA(+)KTS(+), 17AA(+)KTS(−), 17AA(−)KTS(+), and 17AA(−)KTS(−). Here, we showed that 17AA(+)WT1-specific siRNA induced apoptosis in three WT1-expressing leukemia cell lines (K562, HL-60, and Kasumi-1), but not in WT1-non-expressing lymphoma cell line (Daudi). 17AA(+)WT1-specific siRNA activated caspase-3 and -9 in the intrinsic apoptosis pathway but not caspase-8 in the extrinsic one. On the other hand, 17AA(−)WT1-specific siRNA did not induce apoptosis in the three WT1-expressing cell lines. The apoptosis was associated with activation of proapoptotic Bax, which was activated upstream of the mitochondria. Constitutive expression of 17AA(+)WT1 isoforms inhibited apoptosis of K562 leukemia cells induced by apoptosis-inducing agents, etoposide and doxorubicin, through the protection of mitochondrial membrane damages, and DNA-binding zinc-finger region of 17AA(+)WT1 isoform was essential for the antiapoptotic functions. We further studied the gene(s) whose expression was altered by the expression of 17AA(+)WT1 isoforms and showed that the expression of proapoptotic Bak was decreased by the expression of 17AA(+)KTS(−)WT1 isoform. Taken together, these results indicated that 17AA(+)WT1 isoforms played antiapoptotic roles at some points upstream of the mitochondria in the intrinsic apoptosis pathway.

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References

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

  • Call KM, Glaser TM, Ito CY, Buckler AJ, Pelletier J, Haber DA et al. (1990). Cell 60: 509–520.

  • Davies JA, Ladomery M, Hohenstein P, Michael L, Shafe A, Spraggon L et al. (2004). Hum Mol Genet 13: 235–246.

  • Davies RC, Calvio C, Bratt E, Larsson SH, Lamond AI, Hastie ND . (1998). Genes Dev 12: 3217–3225.

  • Drummond IA, Madden SL, Rohwer-Nutter P, Bell GI, Sukhatme VP, Rauscher III FJ . (1992). Science 257: 674–678.

  • Englert C, Maheswaran S, Garvin AJ, Kreidberg J, Haber DA . (1997). Cancer Res 8: 1429–1434.

  • Gashler AL, Bonthouron DT, Madden SL, Rauscher III FJ, Collins T, Sukhatme VP . (1992). Proc Natl Acad Sci USA 89: 10984–10988.

  • Goodyer P, Dehbi M, Torban E, Bruening W, Pelletier J . (1995). Oncogene 10: 1125–1129.

  • Harada Y, Nonomura N, Nishimura K, Tamaki H, Takahara S, Miki T et al. (1999). Mol Urol 3: 357–364.

  • Harrington MA, Konicek B, Song A, Xia XL, Fredericks WJ, Rauscher III FJ . (1993). J Biol Chem 268: 21271–21275.

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

  • Hubinger G, Schmid M, Linortner S, Manegold A, Bergmann L, Maurer U . (2001). Exp Hematol 10: 1226–1235.

  • Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H et al. (1994). Blood 84: 3071–3079.

  • Inoue K, Tamaki H, Ogawa H, Oka Y, Soma T, Tatekawa T et al. (1998). Blood 91: 2969–2976.

  • Kreidberg JA, Sariola H, Loring JM, Maeda M, Pelletier J, Housman D et al. (1993). Cell 74: 679–691.

  • Larsson SH, Charlieu JP, Miyagawa K, Engelkamp D, Rassoulzadegan M, Ross A et al. (1995). Cell 81: 391–401.

  • Li H, Oka Y, Tsuboi A, Yamagami T, Miyazaki T, Yusa S et al. (2003). Int J Hematol 77: 463–470.

  • Loeb DM, Evron E, Patel CB, Sharma PM, Niranjan B, Buluwela L et al. (2001). Cancer Res 61: 921–925.

  • Loeb DM, Summers JL, Burwell EA, Korz D, Friedman AD, Sukumar S . (2003). Leukemia 17: 965–971.

  • Mayo MW, Wang CY, Drouin SS, Madrid LV, Marshall AF, Reed JC et al. (1999). EMBO J 18: 3990–4003.

  • Miyoshi Y, Ando A, Egawa C, Taguchi T, Tamaki Y, Tamaki H et al. (2002). Clin Cancer Res 8: 1167–1171.

  • Niksic M, Slight J, Sanford JR, Caceres JF, Hastie ND . (2004). Hum Mol Genet 13: 463–471.

  • Oji Y, Inohara H, Nakazawa M, Nakano Y, Akahani S, Nakatsuka S et al. (2003a). Cancer Sci 94: 523–529.

  • Oji Y, Miyoshi S, Maeda H, Hayashi S, Tamaki H, Nakatsuka S et al. (2002). Int J Cancer 100: 297–303.

  • Oji Y, Miyoshi Y, Koga S, Nakano Y, Ando A, Nakatsuka S et al. (2003b). Cancer Sci 94: 606–611.

  • Oji Y, Nakamori S, Fujikawa M, Nakatsuka S, Yokota A, Tatsumi N et al. (2004a). Cancer Sci 95: 583–587.

  • Oji Y, Ogawa H, Tamaki H, Oka Y, Tsuboi A, Kim EH et al. (1999). Jpn J Cancer Res 90: 194–204.

  • Oji Y, Suzuki T, Nakano Y, Maruno M, Nakatsuka S, Jomgeow T et al. (2004b). Cancer Sci 95: 822–827.

  • Oji Y, Yamamoto H, Nomura M, Nakano Y, Ikeba A, Nakatsuka S et al. (2003c). Cancer Sci 94: 712–717.

  • Oji Y, Yano M, Nakano Y, Abeno S, Nakatsuka S, Ikeba A et al. (2004c). Anticancer Res 24: 3103–3108.

  • Osaka M, Koami K, Sugiyama T . (1997). Int J Cancer 72: 696–699.

  • Reynolds PA, Smolen GA, Palmer RE, Sgroi D, Yajnik V, Gerald WL et al. (2003). Genes Dev 17: 2094–2107.

  • Shimizu S, Eguchi Y, Kamiike W, Matsuda H, Tsujimoto Y . (1996). Oncogene 12: 2251–2257.

  • Siehl JM, Reinwald M, Heufelder K, Menssen HD, Keilholz U, Thiel E . (2000). Ann Hematol 83: 745–750.

  • Sugiyama H . (2001). Int J Hematol 73: 177–187.

  • Tsuboi A, Oka Y, Ogawa H, Elisseeva OA, Tamaki H, Oji Y et al. (1999). Leuk Res 23: 499–505.

  • Tuna M, Chavez-Reyes A, Tari AM . (2005). Oncogene 24: 1648–1652.

  • Ueda T, Oji Y, Naka N, Nakano Y, Takahashi E, Koga S et al. (2003). Cancer Sci 3: 271–276.

  • Wagner KD, Wagner N, Vidal VP, Schley G, Wilhelm D, Schedl A et al. (2002). EMBO J 21: 1398–1405.

  • Werner H, Re GG, Drummond IA, Sukhatme VP, Rauscher III FJ, Sens DA et al. (1993). Proc Natl Acad Sci USA 90: 5828–5832.

  • Yamagami T, Ogawa H, Tamaki H, Oji Y, Soma T, Oka Y et al. (1998). Leuk Res 22: 383–384.

  • Yamagami T, Sugiyama H, Inuoe K, Ogawa H, Tatekawa T, Hirata M et al. (1996). Blood 87: 2878–2884.

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Acknowledgements

This work was supported in part by a Grant-in Aid from the Ministry of Education, Science, Sports and Culture and the Ministry of Health, Labour, and Welfare, Japan.

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Correspondence to H Sugiyama.

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Ito, K., Oji, Y., Tatsumi, N. et al. Antiapoptotic function of 17AA(+)WT1 (Wilms' tumor gene) isoforms on the intrinsic apoptosis pathway. Oncogene 25, 4217–4229 (2006). https://doi.org/10.1038/sj.onc.1209455

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