Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes (original) (raw)

Nature Cell Biology volume 6, pages 1221–1228 (2004)Cite this article

Abstract

Programmed cell death can be divided into several categories including type I (apoptosis) and type II (autophagic death)1,2. The Bcl-2 family of proteins are well-characterized regulators of apoptosis3, and the multidomain pro-apoptotic members of this family, such as Bax and Bak, act as a mitochondrial gateway where a variety of apoptotic signals converge4,5,6. Although embryonic fibroblasts from Bax/Bak double knockout mice are resistant to apoptosis4,5,6, we found that these cells still underwent a non-apoptotic death after death stimulation. Electron microscopic and biochemical studies revealed that double knockout cell death was associated with autophagosomes/autolysosomes. This non-apoptotic death of double knockout cells was suppressed by inhibitors of autophagy, including 3-methyl adenine, was dependent on autophagic proteins APG5 and Beclin 1 (capable of binding to Bcl-2/Bcl-xL), and was also modulated by Bcl-xL. These results indicate that the Bcl-2 family of proteins not only regulates apoptosis, but also controls non-apoptotic programmed cell death that depends on the autophagy genes.

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Acknowledgements

We are grateful to S. J. Korsmeyer for providing SV40-immortalized Bax/Bak −/− MEFs. This study was supported in part by grants for Scientific Research on Priority Areas, Center of Excellence Research, the twenty-first century COE Program, and Scientific Research, from the Ministry of Education, Science, Sports and Culture of Japan, and by a grant for Research on Dementia and Fracture from the Ministry of Health, Labour and Welfare of Japan.

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Authors and Affiliations

  1. Department of Post-Genomics & Diseases, Osaka University Medical School, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
    Shigeomi Shimizu, Takeshi Mizuta & Yoshihide Tsujimoto
  2. CREST of the Japan Science and Technology Corporation (JST), 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
    Shigeomi Shimizu & Yoshihide Tsujimoto
  3. SORST of the Japan Science and Technology Corporation (JST), 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
    Shigeomi Shimizu, Takeshi Mizuta & Yoshihide Tsujimoto
  4. Department of Cell Biology, National Institute for Basic Biology, Okazaki, 444-8585, Aichi, Japan
    Toku Kanaseki, Noboru Mizushima & Satoko Arakawa-Kobayashi
  5. PRESTO of the Japan Science and Technology Corporation (JST), Okazaki, 444-8585, Aichi, Japan
    Noboru Mizushima
  6. Department of Bioregulation and Metabolism, The Tokyo Metropolitan Institute of Medical Science, Tokyo, 113-8613, Japan
    Noboru Mizushima
  7. Departments of Medicine and Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, 19104, PA, USA
    Craig B. Thompson

Authors

  1. Shigeomi Shimizu
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  2. Toku Kanaseki
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  3. Noboru Mizushima
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  4. Takeshi Mizuta
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  5. Satoko Arakawa-Kobayashi
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  6. Craig B. Thompson
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  7. Yoshihide Tsujimoto
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Correspondence toYoshihide Tsujimoto.

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Shimizu, S., Kanaseki, T., Mizushima, N. et al. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes.Nat Cell Biol 6, 1221–1228 (2004). https://doi.org/10.1038/ncb1192

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