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TNFa-Induced Apoptosis Enabled by CCN1/CYR61: Pathways of Reactive Oxygen Species Generation and Cytochrome c Release

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Title: TNFa-Induced Apoptosis Enabled by CCN1/CYR61: Pathways of Reactive Oxygen Species Generation and Cytochrome c Release
Author(s): Juric, Vladislava; Chen, Chih-Chiun; Lau, Lester F.
Abstract: Although TNFa is a strong inducer of apoptosis, its cytotoxicity in most normal cells in vitro requires blockade of NFkB signaling or inhibition of de novo protein synthesis, typically by the addition of cycloheximide. However, several members of CCN (CYR61/CTGF/NOV) family of extracellular matrix proteins enable TNFa-dependent apoptosis in vitro without inhibiting NFkB or de novo protein synthesis, and CCN1 (CYR61) is essential for optimal TNFa cytotoxicity in vivo. Previous studies showed that CCN1 unmasks the cytotoxicity of TNFa by binding integrins avb5, a6b1, and the cell surface heparan sulfate proteoglycan syndecan 4 to induce the accumulation of a high level of reactive oxygen species (ROS), leading to a biphasic activation of JNK necessary for apoptosis. Here we show for the first time that CCN1 interacts with the low density lipoprotein receptor-related protein 1 (LRP1) in a protein complex, and that binding to LRP1 is critical for CCN1-induced ROS generation and apoptotic synergism with TNFa. We also found that neutral sphingomyelinase 1 (nSMase1), which contributes to CCN1-induced ROS generation, is required for CCN1/TNFa-induced apoptosis. Furthermore, CCN1 promotes the activation of p53 and p38 MAPK, which mediate enhanced cytochrome c release to amplify the cytotoxicity of TNFa. By contrast, LRP1, nSMase1, p53, and p38 MAPK are not required when TNFa-dependent apoptosis is facilitated by the presence of cycloheximide, indicating that they function in the CCN1 signaling pathway that converges with TNFa-induced signaling events. Since CCN1/CYR61 is a physiological regulator of TNFa cytotoxicity at least in some contexts, these findings may reveal important mediators of TNFa-induced apoptosis in vivo and identify potential therapeutic targets for thwarting TNFa-dependent tissue damage.
Issue Date: 2012-02
Publisher: Public Library of Science
Citation Info: Juric, V., Chen, C. C., & Lau, L. F. 2012. TNFalpha-Induced Apoptosis Enabled by CCN1/CYR61: Pathways of Reactive Oxygen Species Generation and Cytochrome c Release. PLoS One, 7(2): e31303. doi:10.1371/journal.pone.0031303
Type: Article
Description: © 2012 Juric et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
ISSN: 1932-6203
Sponsor: This work was supported by grants GM78492 and HL81390 from the National Institutes of Health ( to LFL. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Date Available in INDIGO: 2012-04-29

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