Abstract
The p38 mitogen-activated protein kinase (MAPK) signaling pathway can be activated by a variety of stress stimuli such as UV radiation and osmotic stress. The regulation and role of this pathway in death receptor-induced apoptosis remain unclear and may depend on the specific death receptor and cell type. Here we show that binding of Fas ligand to Fas activates p38 MAPK in CD8+ T cells and that activation of this pathway is required for Fas-mediated CD8+ T-cell death. Active p38 MAPK phosphorylates Bcl-xL and Bcl-2 and prevents the accumulation of these antiapoptotic molecules within the mitochondria. Consequently, a loss of mitochondrial membrane potential and the release of cytochrome c lead to the activation of caspase 9 and, subsequently, caspase 3. Therefore, the activation of p38 MAPK is a critical link between Fas and the mitochondrial death pathway and is required for the Fas-induced apoptosis of CD8+ T cells.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / metabolism*
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CD8-Positive T-Lymphocytes / pathology
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Caspase 3
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Caspase 9
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Caspases / metabolism
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Cells, Cultured
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Cytochromes c / metabolism
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Fas Ligand Protein
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / pharmacology
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Mice
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Mice, Transgenic
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Mitochondria / metabolism*
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Phosphorylation
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Protein Transport
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Signal Transduction
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Tumor Necrosis Factors / metabolism
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Tumor Necrosis Factors / pharmacology
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bcl-X Protein / metabolism
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fas Receptor / metabolism*
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p38 Mitogen-Activated Protein Kinases / drug effects
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism*
Substances
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Fas Ligand Protein
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Fasl protein, mouse
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Membrane Glycoproteins
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Proto-Oncogene Proteins c-bcl-2
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Tumor Necrosis Factors
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bcl-X Protein
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fas Receptor
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Cytochromes c
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p38 Mitogen-Activated Protein Kinases
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Casp3 protein, mouse
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Casp9 protein, mouse
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Caspase 3
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Caspase 9
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Caspases