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A novel apoptotic pathway induced by the drs tumor suppressor gene

Oncogene volume 23, pages 2977–2987 (2004)Cite this article

Abstract

The drs gene was originally isolated as a suppressor against v-src transformation. Expression of drs mRNA was markedly downregulated in a variety of human cancer cell lines and tissues, suggesting that the drs gene acts as a tumor suppressor. In this study, we found that ectopic expression of the Drs protein induced apoptosis in human cancer cell lines. Analyses using deletion mutants of drs revealed that both the C-terminal region and the three consensus repeats in the N-terminal region are essential for the induction of apoptosis. Caspase-12, -9, and -3 were sequentially activated by drs, and specific inhibitors of caspase-3 and -9 suppressed drs-induced apoptosis. The release of cytochrome c from the mitochondria into the cytoplasm was not observed in apoptosis by drs, suggesting that the mitochondrial pathway does not mediate drs-induced apoptosis. Furthermore, we found that the Drs protein can interact with ASY/Nogo-B/RTN-xS, an apoptosis-inducing protein localized in the endoplasmic reticulum, and that coexpression of these genes increased the efficiency of apoptosis. These results indicated that Drs induces apoptosis by a novel pathway mediated by ASY/Nogo-B/RTN-xS, caspase-12, -9, and -3.

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Acknowledgements

We thank Hiroshi Okuno and Takefumi Yamamoto (Central Research Laboratory, Shiga University of Medical Science) for technical assistance. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas (C) (Grant No. 14028032), and a Grant-in-Aid for Scientific Research (C) (Grant No. 13670211) from the Ministry of Education, Science, Sports, and Culture of Japan (H. Inoue). This work was also supported by a grant from the NOVARTIS Foundation (Japan) for the Promotion of Science (H. Inoue).

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  1. Atsuko Yoshioka-Yamashita

    Present address: Division of Biological Sciences, University of California, San Diego, La Jolla, CA, 92093-0322, USA

Authors and Affiliations

  1. Department of Microbiology, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan

    Yukihiro Tambe, Seiki Haraguchi, Atsuko Yoshioka-Yamashita & Hirokazu Inoue

  2. Central Research Laboratory, Shiga University of Medical Science, Otsu, Shiga, 520-2192, Japan

    Takahiro Isono

  3. Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, 565-0871, Japan

    Masuo Yutsudo

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  1. Yukihiro Tambe
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Correspondence to Hirokazu Inoue.

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Tambe, Y., Isono, T., Haraguchi, S. et al. A novel apoptotic pathway induced by the drs tumor suppressor gene. Oncogene 23, 2977–2987 (2004). https://doi.org/10.1038/sj.onc.1207419

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