ArticlePloS one2012
TNFα-induced apoptosis enabled by CCN1/CYR61: pathways of reactive oxygen species generation and cytochrome c release.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 50 citations in OpenAlex.
- Gut microbes and their metabolites in relation to the classic tumor suppressor gene P53: a novel narrative.NPJ biofilms and microbiomes · 2025Review
- CCN Proteins as Matricellular Regulators of Bone in Aging and Disease.Current osteoporosis reports · 2025Review
- Novel insights into the multifaceted and tissue-specific roles of the endocytic receptor LRP1.The Journal of biological chemistry · 2024Review
- An overview of CCN4 (WISP1) role in human diseases.Journal of translational medicine · 2024Review
- Human Skin Aging and the Anti-Aging Properties of Retinol.Biomolecules · 2023Review
- Role of Oxidative Stress on Insulin Resistance in Diet-Induced Obesity Mice.International journal of molecular sciences · 2023Article
- Article
- Multiple-Molecule Drug Design Based on Systems Biology Approaches and Deep Neural Network to Mitigate Human Skin Aging.Molecules (Basel, Switzerland) · 2021Article
- The Cyr61 Is a Potential Target for Rotundifuran, a Natural Labdane-Type Diterpene fromOxidative medicine and cellular longevity · 2021Article
- The Dual Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Atherosclerosis.Frontiers in cardiovascular medicine · 2021Review
- Conjunction junction, what's the function? CCN proteins as targets in fibrosis and cancers.American journal of physiology. Cell physiology · 2020Review
- Low Density Receptor-Related Protein 1 Interactions With the Extracellular Matrix: More Than Meets the Eye.Frontiers in cell and developmental biology · 2019Review
- The matricellular protein CCN1 in tissue injury repair.Journal of cell communication and signaling · 2018Review
- Crosstalk between p38 MAPK and caspase-9 regulates mitochondria-mediated apoptosis induced by tetra-α-(4-carboxyphenoxy) phthalocyanine zinc photodynamic therapy in LoVo cells.Oncology reports · 2018Article
- Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer.Antioxidants & redox signaling · 2017Article
- Cell surface receptors for CCN proteins.Journal of cell communication and signaling · 2016Review
- Article
- Upregulated expression of BCL2, MCM7, and CCNE1 indicate cisplatin-resistance in the set of two human bladder cancer cell lines: T24 cisplatin sensitive and T24R2 cisplatin resistant bladder cancer cell lines.Investigative and clinical urology · 2016Article
- Role of LPA and the Hippo pathway on apoptosis in salivary gland epithelial cells.Experimental & molecular medicine · 2014Article
- The role of the CCN family of proteins in female reproduction.Cellular and molecular life sciences : CMLS · 2014Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Although TNFα is a strong inducer of apoptosis, its cytotoxicity in most normal cells in vitro requires blockade of NFκB signaling or inhibition of de novo protein synthesis, typically by the addition of cycloheximide. However, several members of CCN (CYR61/CTGF/NOV) family of extracellular matrix proteins enable TNFα-dependent apoptosis in vitro without inhibiting NFκB or de novo protein synthesis, and CCN1 (CYR61) is essential for optimal TNFα cytotoxicity in vivo. Previous studies showed that CCN1 unmasks the cytotoxicity of TNFα by binding integrins α(v)β(5), α(6)β(1), and the cell surface heparan sulfate proteoglycan syndecan 4 to induce the accumulation of a high level of reactive oxygen species (ROS), leading to a biphasic activation of JNK necessary for apoptosis. Here we show for the first time that CCN1 interacts with the low density lipoprotein receptor-related protein 1 (LRP1) in a protein complex, and that binding to LRP1 is critical for CCN1-induced ROS generation and apoptotic synergism with TNFα. We also found that neutral sphingomyelinase 1 (nSMase1), which contributes to CCN1-induced ROS generation, is required for CCN1/TNFα-induced apoptosis. Furthermore, CCN1 promotes the activation of p53 and p38 MAPK, which mediate enhanced cytochrome c release to amplify the cytotoxicity of TNFα. By contrast, LRP1, nSMase1, p53, and p38 MAPK are not required when TNFα-dependent apoptosis is facilitated by the presence of cycloheximide, indicating that they function in the CCN1 signaling pathway that converges with TNFα-induced signaling events. Since CCN1/CYR61 is a physiological regulator of TNFα cytotoxicity at least in some contexts, these findings may reveal important mediators of TNFα-induced apoptosis in vivo and identify potential therapeutic targets for thwarting TNFα-dependent tissue damage.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.