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

Oncogene volume 25, pages 4217–4229 (2006)Cite this article

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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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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Authors and Affiliations

  1. Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    K Ito, N Tatsumi, Y Kanai, T Nakazawa, T Jomgeow, S Aoyagi, Y Nakano, N Sakaguchi & H Sugiyama

  2. Department of Biomedical Informatics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    Y Oji

  3. Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    S Shimizu & Y Tsujimoto

  4. Department of Molecular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    M Asada, H Tamaki, T Shirakata & Y Oka

  5. Department of Cancer Immunotherapy, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    S Nishida, M Kawakami & A Tsuboi

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  1. K Ito
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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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