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The extracellular matrix protein CCN1 dictates TNFα and FasL cytotoxicity in vivo. | LitMetric

The extracellular matrix protein CCN1 dictates TNFα and FasL cytotoxicity in vivo.

Adv Exp Med Biol

Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, 900 S. Ashland Avenue, Chicago, IL 60607, USA.

Published: April 2011

AI Article Synopsis

Article Abstract

It has long been appreciated that the apoptotic activity of TNFα is context-dependent, and requires inhibition of NFκB signaling or protein synthesis to be manifested in most normal cells in culture. Recent studies have uncovered an unexpected pro-apoptotic synergism between TNF cytokines and the CCN family of extracellular matrix proteins, which are dynamically expressed at sites of injury repair and inflammation. The presence of CCN1, CCN2, or CCN3 allows TNFα to induce apoptosis with high efficacy without perturbation of NFκB signaling or protein synthesis, thus converting TNFα from a proliferation-promoting protein into an apoptotic inducer. CCN proteins also enhance the cytotoxicity of other TNF family cytokines including LTα, FasL, and TRAIL. CCN proteins synergize with TNF cytokines through binding to integrin αβ and the heparan sulfate proteoglycan (HSPG) syndecan-4 to induce reactive oxygen species (ROS) accumulation. Knockin mice that express a CCN1 mutant defective for binding αβ-HSPG are severely blunted in TNFα- and Fas-mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. Thus, CCN proteins in the extracellular matrix microenvironment can provide the contextual cues for the cytotoxicity of TNFα and related cytokines, and profoundly influence their activity.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646414PMC
http://dx.doi.org/10.1007/978-1-4419-6612-4_63DOI Listing

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