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Bcl-2 attenuation of oxidative cell death is associated with up-regulation of gamma-glutamylcysteine ligase via constitutive NF-kappa B activation

Cited 52 time in Web of Science Cited 57 time in Scopus
Authors
Jang, Jung-Hee; Surh, Young-Joon
Issue Date
2004-09
Citation
Journal of Biological Chemistry, Vol.279 No.37, pp.38779-38786
Abstract
Oxidative stress induced by reactive oxygen intermediates often causes cell death via apoptosis, which is regulated by many functional genes and their protein products. The evolutionarily conserved protein Bcl-2 blocks apoptosis induced by a wide array of death signals. Despite extensive research, the molecular milieu that characterizes the anti-apoptotic function of Bcl-2 has not been fully clarified. In this work, we have investigated the role of bcl-2 in protecting against oxidative death induced by H2O2 in cultured rat pheochromocytoma PC12 cells. Transfection with the bcl-2 gene rescued PC12 cells from apoptotic death caused by H2O2. Addition of NF-kappaB inhibitors such as pyrrolidine dithiocarbamate and N-tosyl-L-phenylalanine chloromethyl ketone to the medium aggravated oxidative cell death. PC12 cells overexpressing bcl-2 exhibited relatively high constitutive DNA binding and transcriptional activities of NF-kappaB compared with vector-transfected control cells. Western blot analysis and immunocytochemistry revealed that bcl-2-transfected PC12 cells retained a higher level of p65 (the functionally active subunit of NF-kappaB) in the nucleus compared with vector-transfected controls. In addition, sustained activation of ERK1/2 (upstream of NF-kappaB) was observed in bcl-2-overexpressing cells. In contrast, the cytoplasmic inhibitor IkappaBalpha was present in lower amounts in cells overexpressing bcl-2. The ectopic expression of bcl-2 increased the cellular glutathione level and gamma-glutamylcysteine ligase expression, which were attenuated by NF-kappaB inhibitors. These results suggest that NF-kappaB plays a role in bcl-2-mediated protection against H2O2-induced apoptosis in PC12 cells through augmentation of antioxidant capacity.
ISSN
0021-9258
URI
https://hdl.handle.net/10371/172834
DOI
https://doi.org/10.1074/jbc.M406371200
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Graduate School of Convergence Science and Technology (융합과학기술대학원)Dept. of Molecular and Biopharmaceutical Sciences (분자의학 및 바이오제약학과)Journal Papers (저널논문_분자의학 및 바이오제약학과)
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