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  • Original Paper
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ASK1 mediates apoptotic cell death induced by genotoxic stress

Oncogene volume 18, pages 173–180 (1999)Cite this article

Abstract

Genotoxic stress-induced apoptosis is mediated by caspase family proteases as triggered by other stimuli. In this study, we found that the DNA-damaging agent cisplatin (cDDP) activated MAP kinase kinase kinase ASK1 and subsequent downstream subgroups of MAP kinase kinase, SEK1 (or MKK4) and MKK3/MKK6, which in turn activated c-Jun N-terminal kinase 1/stress-activated protein kinase (JNK1/SAPK) and p38 MAP kinase prior to caspase family protease activation and the onset of apoptosis in human ovarian carcinoma (OVCAR-3) and human kidney (293T) cells. As reported previously, benzyloxy carbonyl-Asp-CH2OC(O)-2, 6-dichlorobenzene (Z-Asp), a preferential inhibitor of caspase family proteases, blocked the apoptosis of OVCAR-3 cells induced by the genotoxic stress cDDP. Z-Asp, however, did not inhibit ASK1 activation and the subsequent kinase cascades. Overexpression of kinase-negative ASK1 (K709R), which inhibited ASK1 activation and the downstream MKK3-p38 and MKK4-JNK1 pathways, also suppressed the caspase protease activation and apoptosis induced by cDDP. These results indicate that the ASK1 pathway is involved in genotoxic stress-induced apoptosis and mediates apoptosis at a step upstream of caspase protease activation.

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Acknowledgements

We thank Drs Hideki Nishitoh, Naoya Fujita, Koji Noguchi, Yongke Zhang and Akihiro Tomida for helpful discussions. This work was supported in part by a special grant for advanced research on cancer, grants-in-aid from the Ministry of Education, Science, Sports and Culture, Japan and the Organization for Pharmaceutical Safety and Research (OPSR), and the Vehicle Racing Commemorative Foundation, Japan.

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Authors and Affiliations

  1. Laboratory of Biomedical Research, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, 113, Tokyo, Japan

    Zhihong Chen, Mikihiko Naito, Tetsuo Mashima, Atsuo Kizaki, Shingo Dan & Takashi Tsuruo

  2. Cancer Chemotherapy Center, The Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, 170, Tokyo, Japan

    Hiroyuki Seimiya, Miki Imaizumi & Takashi Tsuruo

  3. Department of Biochemistry, The Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-ku, 170, Tokyo, Japan

    Hidenori Ichijo & Kohei Miyazono

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  1. Zhihong Chen
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Chen, Z., Seimiya, H., Naito, M. et al. ASK1 mediates apoptotic cell death induced by genotoxic stress. Oncogene 18, 173–180 (1999). https://doi.org/10.1038/sj.onc.1202276

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