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  • Original Paper
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Activation of c-Abl tyrosine kinase requires caspase activation and is not involved in JNK/SAPK activation during apoptosis of human monocytic leukemia U937 cells

Oncogene volume 18, pages 1277–1283 (1999)Cite this article

Abstract

Genotoxic stress triggers the activation of several sensor molecules, such as p53, JNK1/SAPK and c-Abl, and occasionally promotes the cells to apoptosis. We previously reported that JNK1/SAPK regulates genotoxic stress-induced apoptosis in p53-negative U937 cells by activating caspases. c-Abl is expected to act upstream of JNK1/SAPK activation upon treatment with genotoxic stressors, but its involvement in apoptosis development is still unclear. We herein investigated the kinase activities of c-Abl and JNK1/SAPK during apoptosis elicited by genotoxic anticancer drugs and tumor necrosis factor (TNF) in U937 cells and their apoptosis-resistant variant UK711 cells. We found that the activation of JNK1/SAPK and c-Abl correlated well with apoptosis development in these cell lines. Unexpectedly, however, the JNK1/SAPK activation preceded the c-Abl activation. Moreover, the caspase inhibitor Z-Asp suppressed c-Abl activation and the onset of apoptosis but not the JNK1/SAPK activation. Interestingly, c-Abl tyrosine kinase inhibition by CGP 57148 reduced apoptosis without interfering with JNK1/SAPK activation. These results indicate that c-Abl acts not upstream of JNK1/SAPK but downstream of caspases during the development of p53-independent apoptosis and is possibly involved in accelerating execution of the cell death pathway.

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Acknowledgements

We are grateful to Dr Hisamaru Hirai, the 3rd Department of Internal Medicine, Faculty of Medicine, University of Tokyo, for providing us the cDNA coding c-Crk and Novartis Pharma, Inc. for providing us CGP 57148. This work was supported by a special grant for Advanced Research on Cancer from the Ministry of Education, Science and Culture, Japan; the Organization for Pharmaceutical Safety and Research (OPSR), Japan; and the Vehicle Racing Commemorative Foundation, Japan.

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Authors and Affiliations

  1. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1, Yayoi, Bunkyo-Ku, Tokyo, 113-0032

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

  2. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 170-8455, Japan

    Hiroyuki Seimiya & Takashi Tsuruo

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  1. Shingo Dan
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Dan, S., Naito, M., Seimiya, H. et al. Activation of c-Abl tyrosine kinase requires caspase activation and is not involved in JNK/SAPK activation during apoptosis of human monocytic leukemia U937 cells. Oncogene 18, 1277–1283 (1999). https://doi.org/10.1038/sj.onc.1202423

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