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Cytotoxicity of TNFalpha is regulated by integrin-mediated matrix signaling.

The EMBO journal | Mar 7, 2007

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 TNFalpha is cytotoxic to certain tumor cell lines, it induces apoptosis in normal cells only when NFkappaB signaling is blocked. Here we show that the matricellular protein CCN1/CYR61 can unmask the cytotoxic potential of TNFalpha without perturbation of NFkappaB 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 TNFalpha-induced apoptosis in vivo. These results indicate that CCN1 may act as a physiologic regulator of TNFalpha cytotoxicity, providing the contextual cues from the extracellular matrix for TNFalpha-mediated cell death.

Pubmed ID: 17318182 RIS Download

Mesh terms: Animals | Apoptosis | Caspase 3 | Cells, Cultured | Cysteine-Rich Protein 61 | Fibroblasts | Humans | Immediate-Early Proteins | Infant, Newborn | Integrins | JNK Mitogen-Activated Protein Kinases | Mice | Mice, Knockout | Models, Biological | Mutation | NADPH Oxidase | NF-kappa B | RNA, Small Interfering | Reactive Oxygen Species | Signal Transduction | Tumor Necrosis Factor-alpha

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA046565-17
  • Agency: NHLBI NIH HHS, Id: T32 HL07829
  • Agency: NHLBI NIH HHS, Id: T32 HL007829
  • Agency: NCI NIH HHS, Id: R01 CA046565
  • Agency: NCI NIH HHS, Id: CA46565

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