Gene dosage-dependent effects of bcl-2 expression on cellular survival and redox status

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-leve...

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Bibliographic Details
Published in:Free radical biology & medicine 2003-06, Vol.34 (12), p.1517-1530
Main Authors: Seyfried, Jan, Evert, Bernd O, Schwarz, Cordelia S, Schaupp, Matthias, Schulz, Jörg B, Klockgether, Thomas, Wüllner, Ullrich
Format: Article
Language:English
Subjects:
Animals
Antioxidant
Antioxidants - metabolism
Apoptosis
Bcl-2
Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors
Cell Survival - physiology
Dopamine Agents - pharmacology
Doxycycline - pharmacology
Enzyme Inhibitors - pharmacology
Flavonoids - pharmacology
Free radicals
Gene Dosage
Gene Expression Regulation - physiology
Glutathione
Glutathione - analysis
Levodopa - pharmacology
Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinases - metabolism
Neurodegeneration
Oxidation-Reduction
Oxidative Stress
PC 12 cells
PC12 Cells - cytology
PC12 Cells - metabolism
Phosphorylation
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Rats
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Summary: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.
ISSN:0891-5849
1873-4596
DOI:10.1016/S0891-5849(03)00103-5