Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 37, Issue 5, Pages 632-642Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2004.05.027
Keywords
glutathione; glutamate-cysteine ligase; tumor necrosis factor; apoptosis; mitochondria; free radicals
Funding
- NCI NIH HHS [1R29CA75316, 1R01CA90473, 1R01CA74131, 1R01CA23226] Funding Source: Medline
- NIA NIH HHS [1P01AG01751] Funding Source: Medline
- NIEHS NIH HHS [1T32ES07032, 1P30ES07033, 1P42ES04696] Funding Source: Medline
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Glutathione (GSH) is important in free radical scavenging, maintaining cellular redox status, and regulating cell survival in response to a wide variety of toxicants. The rate-limiting enzyme in GSH synthesis is glutamate-cysteine ligase (GCL), which is composed of catalytic (GCLC) and modifier (GCLM) subunits. To determine whether increased GSH biosynthetic capacity enhances cellular resistance to tumor necrosis factor-alpha- (TNF-alpha-) induced apoptotic cell death, we have established several mouse liver hepatoma (Hepa- 1) cell lines overexpressing GCLC and/or GCLM. Cells overexpressing GCLC alone exhibit modest increases in GCL activity, while cells overexpressing both subunits have large increases in GCL activity. Importantly, cells overexpressing both GCL subunits exhibit increased resistance to TNF-induced apoptosis as judged by a loss of redox potential; mitochondrial membrane potential; translocation of cytochrome c to the cytoplasm; and activation of caspase-3, caspase-8, and caspase-9. Analysis of the effects of TNF on these parameters indicates that maintaining mitochondrial integrity mediates this protective effect in GCL-overexpressing cells. (C) 2004 Elsevier Inc. All rights reserved.
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