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Involvement of JNK in the regulation of autophagic cell death

Oncogene volume 29, pages 2070–2082 (2010)Cite this article

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Abstract

Programmed cell death is a crucial process in the normal development and physiology of metazoans, and it can be divided into several categories that include type I death (apoptosis) and type II death (autophagic cell death). The Bcl-2 family proteins are well-characterized regulators of apoptosis, among which multidomain pro-apoptotic members (such as Bax and Bak) function as a mitochondrial gateway at which various apoptotic signals converge. Although embryonic fibroblasts from Bax/Bak double-knockout (DKO) mice are resistant to apoptosis, we have previously reported that these cells still die by autophagy in response to various death stimuli. In this study, we found that jun N-terminal kinase (JNK) was activated in etoposide- and staurosporine-treated, but not serum-starved, Bax/Bak DKO cells, and that autophagic cell death was suppressed by the addition of a JNK inhibitor and by a dominant-negative mutant of JNK. Studies with sek1−/−mkk7−/− cells revealed that disruption of JNK prevented the induction of autophagic cell death. Co-activation of JNK and autophagy induced autophagic cell death. Activation of JNK occurred downstream of the induction of autophagy, and was dependent on the autophagic process. These results indicate that JNK activation is crucial for the autophagic death of Bax/Bak DKO cells.

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Acknowledgements

We thank Dr N Mizushima for providing us with MEFs from Atg5−/− and Atg5+/+ mice and pCAGGS-GFP-LC3 plasmid. We also thank Drs R Davis and Y Gotoh for providing PCMV5-JNK1 APF plasmid and pCDNA3 MKK7-JNK1 WT plasmid, respectively. This study was partly supported by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO); a grant for Scientific Research on Priority Areas, SORST of Japan Science and Technology Corp; a grant for the 21st Century COE Program; a grant for Creative Scientific Research from the Japanese Ministry of Education, Science, Sports and Culture; and a grant for Comprehensive Research on Aging and Health from the Japanese Ministry of Health, Labor and Welfare. This study was also supported by grants from the Uehara Memorial Foundation and the Naito Foundation.

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Authors and Affiliations

  1. Department of Medical Genetics, Osaka University Medical School,Yamada-oka, Suita, Osaka, Japan

    S Shimizu, Y Nishida & Y Tsujimoto

  2. Department of Pathological Cell Biology, Medical Research Institute, Tokyo Medical and Dental University,Yushima, Bunkyo-ku, Tokyo, Japan

    S Shimizu, Y Nishida & T Mizuta

  3. Medical Top Track Program, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan

    A Konishi

  4. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan

    H Nishina

  5. Department of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan

    A Yamamoto

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  1. S Shimizu
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  2. A Konishi
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  4. T Mizuta
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Correspondence to S Shimizu or Y Tsujimoto.

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Shimizu, S., Konishi, A., Nishida, Y. et al. Involvement of JNK in the regulation of autophagic cell death. Oncogene 29, 2070–2082 (2010). https://doi.org/10.1038/onc.2009.487

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