期刊
ONCOGENE
卷 27, 期 10, 页码 1366-1375出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210783
关键词
BIK; Bcl-2; autophagy; Beclin-1; LC3
资金
- NCI NIH HHS [R01 CA073803, CA-73803, R01 CA073803-08, R01 CA033616, R21 CA116262, R01 CA033616-27, CA-116262, R21 CA116262-01, CA-33616] Funding Source: Medline
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 expressingB IK 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.
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