Abstract |
Hypoxia/reoxygenation causes cell death, yet the underlying regulatory mechanisms remain partially understood. Recent studies demonstrate that hypoxia/reoxygenation can activate death receptor and mitochondria-dependent apoptotic pathways, involving Bid and Bax mitochondrial translocation and cytochrome c release. Using mouse lung endothelial cells (MLEC), we examined the role of FLIP, an inhibitor of caspase 8, in hypoxia/reoxygenation-induced cell death. FLIP protected MLEC against hypoxia/reoxygenation by blocking both caspase 8/Bid and Bax/mitochondrial apoptotic pathways. FLIP inhibited Bax activation in wild-type and Bid(-/-) MLEC, indicating independence from the caspase 8/Bid pathway. FLIP also inhibited the expression and activation of protein kinase C (PKC) (alpha, zeta) during hypoxia/reoxygenation and promoted an association of inactive forms of PKC with Bax. Surprisingly, FLIP expression also inhibited death-inducing signal complex (DISC) formation in the plasma membrane and promoted the accumulation of the DISC in the Golgi apparatus. FLIP expression also upregulated Bcl-X(L), an antiapoptotic protein. In conclusion, FLIP decreased DISC formation in the plasma membrane by blocking its translocation from the Golgi apparatus and inhibited Bax activation through a novel PKC-dependent mechanism. The inhibitory effects of FLIP on Bax activation and plasma membrane DISC formation may play significant roles in protecting endothelial cells from the lethal effects of hypoxia/reoxygenation.
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Authors | Xue Wang, Yong Wang, Jinglan Zhang, Hong Pyo Kim, Stefan W Ryter, Augustine M K Choi |
Journal | Molecular and cellular biology
(Mol Cell Biol)
Vol. 25
Issue 11
Pg. 4742-51
(Jun 2005)
ISSN: 0270-7306 [Print] United States |
PMID | 15899875
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- BAX protein, human
- BH3 Interacting Domain Death Agonist Protein
- BID protein, human
- Bax protein, mouse
- Bid protein, mouse
- CASP8 and FADD-Like Apoptosis Regulating Protein
- CFLAR protein, human
- Carrier Proteins
- Caspase Inhibitors
- Cflar protein, mouse
- Death Domain Receptor Signaling Adaptor Proteins
- Intracellular Signaling Peptides and Proteins
- Proto-Oncogene Proteins c-bcl-2
- Receptors, Tumor Necrosis Factor
- bcl-2-Associated X Protein
- Protein Kinase C
- CASP8 protein, human
- Casp8 protein, mouse
- Caspase 8
- Caspases
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Topics |
- Animals
- Apoptosis
- BH3 Interacting Domain Death Agonist Protein
- CASP8 and FADD-Like Apoptosis Regulating Protein
- Carrier Proteins
(antagonists & inhibitors, metabolism)
- Caspase 8
- Caspase Inhibitors
- Caspases
(metabolism)
- Cell Hypoxia
- Cell Membrane
(metabolism)
- Death Domain Receptor Signaling Adaptor Proteins
- Endothelial Cells
(metabolism)
- Humans
- Intracellular Signaling Peptides and Proteins
(genetics, metabolism)
- Lung
(cytology)
- Mice
- Protein Kinase C
(metabolism)
- Protein Transport
- Proto-Oncogene Proteins c-bcl-2
(antagonists & inhibitors, metabolism)
- Receptors, Tumor Necrosis Factor
(metabolism)
- bcl-2-Associated X Protein
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