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Article

  • The EMBO Journal (2007) 26, 1257 - 1267
  • doi:10.1038/sj.emboj.7601596

Published online: 22 February 2007

Cytotoxicity of TNFalpha is regulated by integrin-mediated matrix signaling

Chih-Chiun Chen1,a, Jennifer L Young1,a, Ricardo I Monzon1, Ningyu Chen1, Viktor Todorovic acute1 and Lester F Lau1

  1. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL, USA

Correspondence to:

Lester F Lau, Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, 900 South Ashland Avenue, Chicago, IL 60607, USA. Tel.: +1 312 996 6978; Fax: +1 312 996 7034; E-mail: lflau@uic.edu

aCo-first authors

Received 13 April 2006; Accepted 12 January 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 alphavbeta5, alpha6beta1, 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.

  • Keywords:

    • CCN2,
    • CCN3,
    • CTGF,
    • NADPH oxidase,
    • wound healing