Letter abstract
Nature Cell Biology 6, 1221 - 1228 (2004)
Published online: 21 November 2004 | doi:10.1038/ncb1192
Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes
Shigeomi Shimizu1,2,3, Toku Kanaseki4, Noboru Mizushima4,5,6, Takeshi Mizuta1,3, Satoko Arakawa-Kobayashi4, Craig B. Thompson7 & Yoshihide Tsujimoto1,2,3
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.
- Department of Post-Genomics & Diseases, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
- CREST of the Japan Science and Technology Corporation (JST), 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
- SORST of the Japan Science and Technology Corporation (JST), 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
- Department of Cell Biology, National Institute for Basic Biology, Okazaki, Aichi 444-8585, Japan.
- PRESTO of the Japan Science and Technology Corporation (JST), Okazaki, Aichi 444-8585, Japan.
- Department of Bioregulation and Metabolism, The Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan.
- Departments of Medicine and Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104 USA.
Correspondence to: Yoshihide Tsujimoto1,2,3 e-mail: tsujimot@gene.med.osaka-u.ac.jp
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