期刊
EMBO JOURNAL
卷 26, 期 5, 页码 1257-1267出版社
WILEY
DOI: 10.1038/sj.emboj.7601596
关键词
CCN2; CCN3; CTGF; NADPH oxidase; wound healing
资金
- NCI NIH HHS [R01 CA046565-17, R01 CA046565, CA46565] Funding Source: Medline
- NHLBI NIH HHS [T32 HL07829, T32 HL007829] Funding Source: Medline
Cytokines of the tumor necrosis factor (TNF) family regulate inflammation and immunity, and a subset of this family can also induce cell death in a context-dependent manner. Although TNF alpha is cytotoxic to certain tumor cell lines, it induces apoptosis in normal cells only when NF kappa B signaling is blocked. Here we show that the matricellular protein CCN1/CYR61 can unmask the cytotoxic potential of TNF alpha without perturbation of NF kappa B signaling or de novo protein synthesis, leading to rapid apoptosis in the otherwise resistant primary human fibroblasts. CCN1 acts through binding to integrins alpha(v)beta(5), alpha(6)beta(1), and syndecan-4, triggering the generation of reactive oxygen species (ROS) through a Rac1-dependent mechanism via 5-lipoxygenase and the mitochondria, leading to the biphasic activation of JNK necessary for apoptosis. Mice with the genomic Ccn1 locus replaced with an apoptosis-defective Ccn1 allele are substantially resistant to TNF alpha-induced apoptosis in vivo. These results indicate that CCN1 may act as a physiologic regulator of TNF alpha cytotoxicity, providing the contextual cues from the extracellular matrix for TNF alpha-mediated cell death.
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