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

S Shimizu, T Kanaseki, N Mizushima, T Mizuta… - Nature cell …, 2004 - nature.com
S Shimizu, T Kanaseki, N Mizushima, T Mizuta, S Arakawa-Kobayashi, CB Thompson
Nature cell biology, 2004nature.com
Programmed cell death can be divided into several categories including type I (apoptosis)
and type II (autophagic death),. The Bcl-2 family of proteins are well-characterized regulators
of apoptosis, 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 converge,,.
Although embryonic fibroblasts from Bax/Bak double knockout mice are resistant to
apoptosis,,, we found that these cells still underwent a non-apoptotic death after death …
Abstract
Programmed cell death can be divided into several categories including type I (apoptosis) and type II (autophagic death),. The Bcl-2 family of proteins are well-characterized regulators of apoptosis, 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 converge,,. Although embryonic fibroblasts from Bax/Bak double knockout mice are resistant to apoptosis,,, 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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