Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes.
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-x(L)), and was also modulated by Bcl-x(L). 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.
Shimizu
Shigeomi
S
Department of Post-Genomics & Diseases, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Kanaseki
Toku
T
Mizushima
Noboru
N
Mizuta
Takeshi
T
Arakawa-Kobayashi
Satoko
S
Thompson
Craig B
CB
Tsujimoto
Yoshihide
Y
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000235:genetics*; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002478:Cells, Cultured; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C102268:ATG5 protein, S cerevisiae; D051017:Apoptosis Regulatory Proteins; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; C494772:BAK1 protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D011506:Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D029701:Saccharomyces cerevisiae Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C025946:3-methyladenine; D005047:Etoposide; D044767:Ubiquitin-Protein Ligases; D000225:Adenine