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Bcl‐xL interrupts oxidative activation of neutral sphingomyelinase
Author(s) -
Okamoto Yasuo,
Obeid Lina M,
Hannun Yusuf A
Publication year - 2002
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(02)03435-x
Subject(s) - sphingomyelin , ceramide , glutathione , intracellular , sphingomyelin phosphodiesterase , biochemistry , chemistry , microbiology and biotechnology , oxidative phosphorylation , biology , enzyme , apoptosis , membrane
Recent studies demonstrate a role for intracellular oxidation in the regulation of neutral sphingomyelinase (N‐SMase). Glutathione (GSH) has been shown to regulate N‐SMase in vitro and in cells. However, it has not been established whether the effects of GSH in cells are due to direct action on N‐SMase. In this study, treatment of human mammary carcinoma MCF‐7 cells with diamide, a thiol‐depleting agent, caused a decrease in intracellular GSH and degradation of sphingomyelin (SM) to ceramide. The SM pool hydrolyzed in response to diamide belonged to the bacterial SMase‐resistant pool of SM. Importantly, pretreatment of MCF‐7 cells with GSH, N ‐acetylcysteine, an antioxidant, or GW69A, a specific N‐SMase inhibitor, prevented diamide‐induced degradation of SM to ceramide, suggesting that intracellular levels of GSH regulate the extent to which SM is degraded to ceramide and that this probably involves a GW69A‐sensitive N‐SMase. Unexpectedly, expression of Bcl‐xL prevented tumor necrosis factor‐α‐induced SM hydrolysis and ceramide accumulation but not the decrease in intracellular GSH. Furthermore, Bcl‐xL inhibited diamide‐induced SM hydrolysis and ceramide accumulation but not the decrease in intracellular GSH. These results suggest that the site of action of Bcl‐xL is downstream of GSH depletion and upstream of ceramide accumulation, and that GSH probably does not exert direct physiologic effects on N‐SMase.