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J. Biol. Chem., Vol. 279, Issue 37, 38779-38786, September 10, 2004

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Bcl-2 Attenuation of Oxidative Cell Death Is Associated with Up-regulation of -Glutamylcysteine Ligase via Constitutive NF-B Activation^*

Jung-Hee Jang and Young-Joon Surh

From the Laboratory of Biochemistry and Molecular Toxicology, College of Pharmacy, Seoul National University, Shinlim-dong, Kwanak-ku, Seoul 151-742, South Korea

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-B 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-B 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-B) in the nucleus compared with vector-transfected controls. In addition, sustained activation of ERK1/2 (upstream of NF-B) was observed in bcl-2-overexpressing cells. In contrast, the cytoplasmic inhibitor IB was present in lower amounts in cells overexpressing bcl-2. The ectopic expression of bcl-2 increased the cellular glutathione level and -glutamylcysteine ligase expression, which were attenuated by NF-B inhibitors. These results suggest that NF-B plays a role in bcl-2-mediated protection against H₂O₂-induced apoptosis in PC12 cells through augmentation of antioxidant capacity.

Received for publication, June 8, 2004 , and in revised form, June 18, 2004.

^* This work was supported by Korea Research Foundation Grant ES0022. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Submitted part of this manuscript in partial fulfillment of the requirements for a Ph.D. degree at the Seoul National University.

To whom correspondence should be addressed. Tel.: 82-2-880-7845; Fax: 82-2-874-9775; E-mail: surh{at}plaza.snu.ac.kr.

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