Open AccessDeadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines
Author(s) -
Chen ChihChiun,
Lau Lester F.
Publication year - 2010
Publication title -
journal of cell communication and signaling
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 44
eISSN - 1873-961X
pISSN - 1873-9601
DOI - 10.1007/s12079-009-0080-4
Subject(s) - matricellular protein , tumor necrosis factor alpha , microbiology and biotechnology , proinflammatory cytokine , apoptosis , biology , fas ligand , immunology , cancer research , chemistry , inflammation , programmed cell death , extracellular matrix , biochemistry
Recent studies have revealed an unexpected synergism between two seemingly unrelated protein families: CCN matricellular proteins and the tumor necrosis factor (TNF) family of cytokines. CCN proteins are dynamically expressed at sites of injury repair and inflammation, where TNF cytokines are also expressed. Although TNFα is an apoptotic inducer in some cancer cells, it activates NFκB to promote survival and proliferation in normal cells, and its cytotoxicity requires inhibition of de novo protein synthesis or NFκB signaling. The presence of CCN1, CCN2, or CCN3 overrides this requirement and unmasks the apoptotic potential of TNFα, thus converting TNFα from a proliferation‐promoting protein into an apoptotic inducer. These CCN proteins also enhance the cytotoxicity of other TNF cytokines, including LTα, FasL, and TRAIL. Mechanistically, CCNs function through integrin α 6 β 1 and the heparan sulfate proteoglycan (HSPG) syndecan‐4 to induce reactive oxygen species (ROS) accumulation, which is essential for apoptotic synergism. Mutant CCN1 proteins defective for binding α 6 β 1 ‐HSPGs are unable to induce ROS or apoptotic synergism with TNF cytokines. Further, knockin mice that express an α 6 β 1 ‐HSPG‐binding defective CCN1 are blunted in TNFα‐ and Fas‐mediated apoptosis, indicating that CCN1 is a physiologic regulator of these processes. These findings implicate CCN proteins as contextual regulators of the inflammatory response by dictating or enhancing the cytotoxicity of TNFα and related cytokines.