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

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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Figure 1: Loss of viability of and induction of autophagy in Bax/Bak−/− MEFs exposed to etoposide and staurosporine.
Figure 2: Inhibition of etoposide-induced death of Bax/Bak−/− MEFs by 3-MA.
Figure 3: Inhibition of etoposide-induced death of Bax/Bak−/− MEFs by silencing autophagy genes.
Figure 4: Occurrence of etoposide-induced, 3-MA-inhibitable, non-apoptotic death in MEFs by overexpressed Bcl-2/Bcl-xL.
Figure 5: Inhibition of non-apoptotic death in etoposide-treated Bax/Bak−/− MEFs by siRNA for Bcl-x.

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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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Correspondence to Yoshihide 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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