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Cited by 70Connective Tissue Growth Factor ResearchCell death mechanisms and regulationSignaling Pathways in Disease

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

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Juric, Vladislava, Chen, Chih-Chiun, Lau, Lester F.·2009·Molecular and Cellular Biology
DOI 10.1128/mcb.00064-09PMC PMC2698731
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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.

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  • CCN1 also strongly enhances the apoptotic activity of other apoptotic members of the TNF family, including FasL and TRAIL.

    “In addition, CCN1 also strongly enhances the apoptotic activity of other apoptotic members of the TNF family, including FasL and TRAIL [77,106].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [106]

  • In contrast to the embryonic lethality of Ccn1-null mice, these knockin mice are viable, fertile, and do not exhibit any obvious developmental defects.

    “In contrast to the embryonic lethality of Ccn1-null mice, these knockin mice are viable, fertile, and do not exhibit any obvious developmental defects.”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [106]

  • In each of these experimental models for TNF-α- or Fas-mediated apoptosis, Ccn1dm/dm mice consistently show a >60% reduction in apoptosis compared with wild-type mice.

    “In each of these experimental models for TNF-α- or Fas-mediated apoptosis, Ccn1dm/dm mice consistently show a >60% reduction in apoptosis compared with wild-type mice [62,106].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [106]

  • The importance of CCN1 in TNF-α- and FasL-induced apoptosis in vivo has been demonstrated using knockin mice (Ccn1dm/dm) in which the genomic Ccn1 locus has been replaced by an apoptosis-defective Ccn1 allele with mutations at the α6β1-HSPG-binding sites.

    “The importance of CCN1 in TNF-α- and FasL-induced apoptosis in vivo has been demonstrated using knockin mice (Ccn1dm/dm) in which the genomic Ccn1 locus has been replaced by an apoptosis-defective Ccn1 allele with mutations at the α6β1–HSPG-binding sites [62,101,106].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [106]

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Authors
Juric, V., Chen, C.-C., & Lau, L. F.
Affiliations
University of Illinois Chicago (US)
Corresponding author
Lau, Lester F.
ORCID
Venue
Molecular and Cellular Biology
Publisher
Informa UK Limited
Published
2009-06-01
Volume
29
Issue
12
Pages
3266-3279
ISSN
  • 0270-7306 (ISSN-L)
  • 1098-5549
DOI
10.1128/mcb.00064-09
PMC
PMC2698731
OpenAlex
W2160860957
Cited by
70
References
72
Citations by year
2026: 3 · 2025: 2 · 2024: 1 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 8
FWCI
3.08
Type
journal article
Language
en
Open access
Licence
journals.asm.org/non-commercial-tdm-license (tdm)
Locations
  • Molecular and Cellular Biology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Heart Association
  • National Institutes of Health
  • National Cancer Institute (R01CA046565, CA-46565, R01CA052220)
  • National Institute of General Medical Sciences (R01GM078492, GM78492)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
Keywords
Fas-mediated apoptosis, Fas ligand, reactive oxygen species, alpha6beta1 integrin, heparan sulfate proteoglycans, p38 MAPK, cytochrome c release, neutral sphingomyelinase, extracellular matrix, hepatic apoptosis, alcohol-induced liver injury, inflammation
MeSH terms
Ethanol, Animals, Base Sequence, Cells, Cultured, Ceramides, Humans, Male, Mice, Inbred C57BL, Mice, Mutant Strains, Models, Biological, Sphingomyelin Phosphodiesterase, Apoptosis, Reactive Oxygen Species, DNA Primers, fas Receptor, Heparan Sulfate Proteoglycans, Hepatocytes, RNA, Small Interfering, Integrin alpha6beta1, Cytochromes c, Mitogen-Activated Protein Kinase 14, Mice, Fas Ligand Protein, Connective Tissue Growth Factor, Cysteine-Rich Protein 61, In Vitro Techniques

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