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Molecular and Cellular Biology, June 2009, p. 3266-3279, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.00064-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Fas-Mediated Apoptosis Is Regulated by the Extracellular Matrix Protein CCN1 (CYR61) In Vitro and In Vivo{triangledown}

Vladislava Juric, Chih-Chiun Chen, and Lester F. Lau*

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

Received 14 January 2009/ Returned for modification 20 February 2009/ Accepted 6 April 2009

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}6β1 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.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60607. Phone: (312) 996-6978. Fax: (312) 996-7034. E-mail: LFLau{at}uic.edu

{triangledown} Published ahead of print on 13 April 2009.

Molecular and Cellular Biology, June 2009, p. 3266-3279, Vol. 29, No. 12
0270-7306/09/$08.00+0     doi:10.1128/MCB.00064-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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