Abstract
Bcl-x(S), a pro-apoptotic member of the Bcl-2 protein family, is localized in the mitochondrial outer membrane and induces caspase-dependent and nerve growth factor (NGF)-inhibitable apoptosis in PC12 cells. The mechanism of action of Bcl-x(S) and how NGF inhibits this death are not fully understood. It is still unknown whether Bcl-x(S) induces mitochondrial cytochrome c release, and which apoptotic step NGF inhibits. We show that Bcl-x(S) induces cytochrome c release and caspase-3 activation in several cell types, and that in PC12 cells, these events are inhibited by NGF treatment. The survival effect of NGF was inhibited by inhibitors of protein kinase C (PKC), phosphatidylinositol-3-kinase (PI 3-kinase), and the mitogen-activated protein kinase kinase (MEK) inhibitors GF109203X, LY294002, and U0126. These findings show that cytochrome c release and caspase-3 activation participate in Bcl-x(S)-induced apoptosis, and that NGF inhibits Bcl-x(S)-induced apoptosis at the mitochondrial level via the PKC, PI 3-kinase, and MEK signaling pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Butadienes / pharmacology
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COS Cells
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Caspases / metabolism
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Cell Survival
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Chlorocebus aethiops
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Chromones / pharmacology
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Cytochromes c / metabolism*
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Enzyme Activation
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Gene Expression
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Indoles / pharmacology
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Maleimides / pharmacology
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / drug effects
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Morpholines / pharmacology
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Nerve Growth Factor / pharmacology*
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Nitriles / pharmacology
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PC12 Cells
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Phosphatidylinositol 3-Kinases / drug effects
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase C / antagonists & inhibitors
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Protein Kinase C / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Rats
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bcl-X Protein
Substances
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Bcl2l1 protein, rat
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Butadienes
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Chromones
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Indoles
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Maleimides
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Morpholines
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Nitriles
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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U 0126
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bcl-X Protein
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Cytochromes c
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Nerve Growth Factor
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Protein Kinase C
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Mitogen-Activated Protein Kinase Kinases
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Caspases
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bisindolylmaleimide I