BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells.
The BH3-only protein BIK normally induces apoptotic cell death. Here, we have investigated the role of BCL-2 in BIK-induced cell death using Bcl-2+/+ and Bcl-2-/- mouse embryo fibroblasts. Ectopic expression of BIK in Bcl-2-/- cells resulted in enhanced cell death compared to Bcl-2+/+ cells. In these cells, while caspase-8 was activated, there was no significant activation of caspase-9 and 3. There was no detectable mitochondrial to cytosolic release of cytochrome-c. However, there was significant redistribution of AIF from mitochondria to the nucleus. The extent of BIK-induced cell death was augmented by treatment with the pancaspase inhibitor, zVAD-fmk. The Bcl-2 null cells expressing BIK exhibited autophagic features such as cytosolic vacuoles, punctate distribution of LC3 and enhanced expression of Beclin-1. The survival of BIK-expressing Bcl-2-/- cells was enhanced in the presence of PI3 kinase inhibitors 3-methyladenine and Wortmannin and also by depletion of Atg5 and Beclin-1. Death of BIK-expressing Bcl-2-/- cells treated with zVAD-fmk was increased under caspase-8 depletion. Our results suggest enhanced expression of BIK in the Bcl-2 deficient cells leads to cell death with autophagic features and the extent of such cell death could be increased by inhibition of caspases.
Rashmi
R
R
Institute for Molecular Virology, Saint Louis University Health Sciences Center, St Louis, MO 63110, USA.
Pillai
S G
SG
Vijayalingam
S
S
Ryerse
J
J
Chinnadurai
G
G
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000235:genetics; D020169:Caspases / Q000502:physiology*; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D019254:Genes, bcl-2; D051379:Mice; D024101:Mitochondrial Proteins / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C111741:Bik protein, mouse; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D020169:Caspases