GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:19364818

From GONUTS
Jump to: navigation, search
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

Significance

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


See also

References

See Help:References for how to manage references in GONUTS.