The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts
Open accessAbstract
Integrin-mediated cell adhesion to extracellular matrix proteins is known to promote cell survival, whereas detachment from the matrix can cause rapid apoptotic death in some cell types. Contrary to this paradigm, we show that fibroblast adhesion to the angiogenic matrix protein CCN1 (CYR61) induces apoptosis, whereas endothelial cell adhesion to CCN1 promotes cell survival. CCN1 induces fibroblast apoptosis through its adhesion receptors, integrin α6β1 and the heparan sulfate proteoglycan (HSPG) syndecan-4, triggering the transcription-independent p53 activation of Bax to render cytochrome c release and activation of caspase-9 and -3. Neither caspase-8 activity nor de novo transcription or translation is required for this process. These results show that cellular interaction with a specific matrix protein can either induce or suppress apoptosis in a cell type–specific manner and that integrin α6β1-HSPGs can function as receptors to induce p53-dependent apoptosis.
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CCN1 induces apoptosis and senescence through integrin α6β1 and heparan sulfate proteoglycans.
“induces apoptosis and senescence through integrin α6β1 and heparan sulfate proteoglycans”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [61]
CCN1 binds HSPGs with high affinity, which serve as co-receptors with integrins in some contexts; syndecan-4 is the critical HSPG for CCN1 functions where examined.
“CCN1 binds HSPGs with high affinity, which serve as co-receptors with integrins in some contexts [13,55]. Where examined, syndecan-4 has been identified as the HSPG critical for CCN1 functions [61,62].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [61]
In fibroblasts, CCN1 triggers apoptosis by binding α6β1 and syndecan-4, leading to p53-dependent activation of Bax and cytochrome c release.
“In fibroblasts, CCN1 triggers apoptosis by binding α6β1 and syndecan-4, leading to the p53-dependent activation of Bax and cytochrome c release, resulting in apoptosis [61].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [61]
Although CCN1 promotes cell survival in endothelial cells and some cancer cells, it represents the first example of an ECM molecule that can induce apoptosis through cell adhesion.
“Although CCN1 promotes cell survival in endothelial cells and some cancer cells [72,81], it represents the first example of an ECM molecule that can induce apoptosis through the process cell adhesion [61].”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [61]
This apoptotic effect is relatively modest in normal fibroblasts but greatly enhanced in cells defective for p21, which are more susceptible to apoptotic signals.
“This effect is relatively modest in normal fibroblasts, but is greatly enhanced in cells that are defective for p21 and are thus more susceptible to apoptotic signals.”
From CCN1/CYR61: the very model of a modern matricellular protein (2011) · cites this paper as [61]
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 [61]
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References 60 · Cited by 132
- Authors
- Todorovicç, V., Chen, C.-C., Hay, N., & Lau, L. F.
- Affiliations
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago College of Medicine, Chicago, IL 60607
- University of Illinois Chicago (US)
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2005-11-07
- Volume
- 171
- Issue
- 3
- Pages
- 559-568
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- OpenAlex
- W2100093802
- Cited by
- 132
- References
- 60
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 3 · 2021: 4 · 2020: 8 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 3 · 2015: 9 · 2014: 13 · 2013: 9 · 2012: 8
- FWCI
- 3.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute on Aging (R01AG016927, AG016927)
- National Cancer Institute (R01CA046565, CA-46565)
- 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
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- CYR61, apoptosis, fibroblasts, alpha6beta1 integrin, syndecan-4, heparan sulfate proteoglycans, p53 activation, Bax, cytochrome c release, caspase-9, caspase-3, endothelial cells
- MeSH terms
- Animals, Cell Survival, Cells, Cultured, Fibroblasts, Humans, Membrane Glycoproteins, Proteoglycans, Protein Biosynthesis, Transcriptional Activation, Tumor Suppressor Protein p53, Apoptosis, Immediate-Early Proteins, Caspases, Intercellular Signaling Peptides and Proteins, Integrin alpha6beta1, Endothelial Cells, Rats, Syndecan-4, Cysteine-Rich Protein 61
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