Abstract
The human oncogene bcl-2 exerts protective functions in numerous models of apoptotic cell death and increased oxidative stress. We investigated the effects of inducible bcl-2 overexpression on cellular survival and redox status in dopaminergic rat pheochromocytoma PC 12 cells. Induction of high-level expression of bcl-2 in PC 12 cells resulted in generation of oxidative stress and cessation of growth by cell cycle arrest. Cell cycle arrest in bcl-2-overexpressing PC 12 cells was prevented by an inhibitor of extracellular signal-related kinase (ERK 1/2) activation. Protective effects of bcl-2 expression against L-DOPA neurotoxicity decreased with increasing amounts of bcl-2. Furthermore, high-level bcl-2 overexpression sensitized cells towards oxidative stress and glutathione depletion. Our data suggest that bcl-2 expression is beneficial only in a limited gene dosage range and that high-level expression of bcl-2 exerts potential deleterious effects.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antioxidants / metabolism
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Cell Survival / physiology*
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Dopamine Agents / pharmacology
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Doxycycline / pharmacology
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Enzyme Inhibitors / pharmacology
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Flavonoids / pharmacology
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Gene Dosage*
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Gene Expression Regulation / physiology*
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Glutathione / analysis
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Levodopa / pharmacology
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Oxidation-Reduction
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Oxidative Stress
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PC12 Cells / cytology
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PC12 Cells / metabolism
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Phosphorylation
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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
Substances
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Antioxidants
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Dopamine Agents
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Enzyme Inhibitors
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Flavonoids
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Proto-Oncogene Proteins c-bcl-2
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Levodopa
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Glutathione
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Doxycycline
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one