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-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.
Seyfried
Jan
J
Department of Neurology, University of Bonn, Bonn, Germany. jan.seyfried@man.ac.uk
Evert
Bernd O
BO
Schwarz
Cordelia S
CS
Schaupp
Matthias
M
Schulz
Jörg B
JB
Klockgether
Thomas
T
Wüllner
Ullrich
U
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002470:Cell Survival / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D018628:Gene Dosage; D005786:Gene Expression Regulation / Q000502:physiology*; D005978:Glutathione / Q000032:analysis; D007980:Levodopa / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D016716:PC12 Cells / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D051381:Rats
D000975:Antioxidants; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D019253:Proto-Oncogene Proteins c-bcl-2; D007980:Levodopa; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione; D004318:Doxycycline; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one