PMID:19364818

Citation	Juric, V, Chen, CC and Lau, LF (2009) Fas-mediated apoptosis is regulated by the extracellular matrix protein CCN1 (CYR61) in vitro and in vivo. Mol. Cell. Biol. 29:3266-79
Abstract	Although Fas ligand (FasL) is primarily expressed by lymphoid cells, its receptor Fas (CD95/Apo-1) is broadly expressed in numerous nonlymphoid tissues and can mediate apoptosis of parenchymal cells upon injury and infiltration of inflammatory cells. Here we show that CCN1 (CYR61) and CCN2 (CTGF), matricellular proteins upregulated at sites of inflammation and wound repair, synergize with FasL to induce apoptosis by elevating cellular levels of reactive oxygen species (ROS). CCN1 acts through engagement of integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans, leading to ROS-dependent hyperactivation of p38 mitogen-activated protein kinase in the presence of FasL to enhance mitochondrial cytochrome c release. We show that CCN1 activates neutral sphingomyelinase, which functions as a key source of CCN1-induced ROS critical for synergism with FasL. Furthermore, Fas-dependent hepatic apoptosis induced by an agonistic monoclonal anti-Fas antibody or intragastric administration of alcohol is severely blunted in knock-in mice expressing an apoptosis-defective Ccn1 allele. These results demonstrate that CCN1 is a physiologic regulator of Fas-mediated apoptosis and that the extracellular matrix microenvironment can modulate Fas-dependent apoptosis through CCN1 expression.
Links	PubMed PMC2698731 Online version:10.1128/MCB.00064-09
Keywords	Animals; Antigens, CD95/metabolism; Apoptosis/physiology; Base Sequence; Cells, Cultured; Ceramides/metabolism; Connective Tissue Growth Factor/metabolism; Cysteine-Rich Protein 61/genetics; Cysteine-Rich Protein 61/metabolism; Cytochromes c/metabolism; DNA Primers/genetics; Ethanol/toxicity; Fas Ligand Protein/metabolism; Heparan Sulfate Proteoglycans/metabolism; Hepatocytes/drug effects; Hepatocytes/metabolism; Hepatocytes/pathology; Humans; Integrin alpha6beta1/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mitogen-Activated Protein Kinase 14/antagonists & inhibitors; Mitogen-Activated Protein Kinase 14/genetics; Mitogen-Activated Protein Kinase 14/metabolism; Models, Biological; RNA, Small Interfering/genetics; Reactive Oxygen Species/metabolism; Sphingomyelin Phosphodiesterase/antagonists & inhibitors; Sphingomyelin Phosphodiesterase/genetics; Sphingomyelin Phosphodiesterase/metabolism
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:ITB1	acts_upstream_of_or_within	GO:0043065: positive regulation of apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P18406	P		Seeded From UniProt	complete
HUMAN:ITB1	acts_upstream_of_or_within	GO:0043065: positive regulation of apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P23229	P		Seeded From UniProt	complete
HUMAN:ITB1	acts_upstream_of_or_within	GO:0043065: positive regulation of apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P48023	P		Seeded From UniProt	complete
MOUSE:CCN1	involved_in	GO:2000304: positive regulation of ceramide biosynthetic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:CCN1	involved_in	GO:0010518: positive regulation of phospholipase activity	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:CCN1	involved_in	GO:0072593: reactive oxygen species metabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:CCN1	involved_in	GO:0043065: positive regulation of apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:O60906	P		Seeded From UniProt	complete
MOUSE:CCN1	involved_in	GO:0043065: positive regulation of apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P05556	P		Seeded From UniProt	complete
MOUSE:CCN1	involved_in	GO:0043065: positive regulation of apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P23229	P		Seeded From UniProt	complete
MOUSE:CCN1	involved_in	GO:0043065: positive regulation of apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P48023	P		Seeded From UniProt	complete
MOUSE:CCN1	involved_in	GO:0043280: positive regulation of cysteine-type endopeptidase activity involved in apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P48023	P		Seeded From UniProt	complete
HUMAN:ITA6	acts_upstream_of_or_within	GO:0043065: positive regulation of apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P05556	P		Seeded From UniProt	complete
HUMAN:ITA6	acts_upstream_of_or_within	GO:0043065: positive regulation of apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P18406	P		Seeded From UniProt	complete
HUMAN:ITA6	acts_upstream_of_or_within	GO:0043065: positive regulation of apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P48023	P		Seeded From UniProt	complete
MOUSE:CCN2	involved_in	GO:0072593: reactive oxygen species metabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:TNFL6	acts_upstream_of_or_within	GO:0006919: activation of cysteine-type endopeptidase activity involved in apoptotic process	ECO:0000316: genetic interaction evidence used in manual assertion	UniProtKB:P18406	P		Seeded From UniProt	complete
MOUSE:CTGF	acts_upstream_of_or_within	GO:0072593: reactive oxygen species metabolic process	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete

References

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