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Cited by 47Connective Tissue Growth Factor ResearchCell death mechanisms and regulationBiomarkers in Disease Mechanisms

Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines

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Chen, Chih‐Chiun, Lau, Lester F.·2010·Journal of Cell Communication and Signaling
DOI 10.1007/s12079-009-0080-4PMC PMC2821476
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Abstract

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.

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  • Physiologically, the apoptotic activities of CCN1 may be most relevant when acting in combination with other apoptotic factors, notably members of the TNF family including TNF-α, FasL, and TRAIL.

    “Physiologically, the apoptotic activities of CCN1 may be most relevant when acting in combination with other apoptotic factors, notably members of the TNF family including TNF-α, FasL, and TRAIL [101].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [101]

  • 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 [101]

  • 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 [101]

  • CCN1 can induce apoptosis.

    “However, CCN1 can also induce apoptosis and cellular senescence [2,61,101], two well-established mechanisms of tumor suppression [155].”

    From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [101]

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Authors
Chen, C., & Lau, L. F.
Affiliations
University of Illinois Chicago (US)
Corresponding author
Lau, Lester F.
ORCID
Lau, Lester F.
Venue
Journal of Cell Communication and Signaling
Publisher
Wiley
Published
2009-11-07
Volume
4
Issue
1
Pages
63-69
ISSN
  • 1873-9601 (ISSN-L)
  • 1873-961X
DOI
10.1007/s12079-009-0080-4
PMC
PMC2821476
OpenAlex
W2168846999
Cited by
47
References
48
Citations by year
2023: 1 · 2022: 2 · 2021: 3 · 2020: 6 · 2019: 2 · 2018: 1 · 2017: 4 · 2016: 1 · 2015: 5 · 2014: 5 · 2013: 5 · 2012: 5
FWCI
1.61
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cell Communication and Signaling (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (CA46565, GM78492, HL81390)
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 › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
Keywords
CYR61, connective tissue growth factor, CCN3, tumor necrosis factor family, TNF-α, apoptosis, NF-κB signaling, alpha6beta1 integrin, syndecan-4, heparan sulfate proteoglycans, reactive oxygen species, Fas ligand, TRAIL, inflammation, injury repair

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