The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts

Todorović, Viktor; Chen, Chih-Chiun; Hay, Nissim; Lau, Lester F.

doi:10.1083/jcb.200504015

Cited by 111 publications

(96 citation statements)

References 62 publications

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“…CCN peptides are ligands of integrins aIIß3 in platelets and avb3 in monocytes [29,30]. CCN1 also interacts with heparinsulfate-containing proteoglycans (HSPGs), including syndecan 4 and perlecan [31,32]. Integrins and HSPGs are essential for the adhesive and mitogenic function of CCN proteins [31,32], and syndecan 4 and integrin a6b1 are necessary for CCN1-mediated induction of apoptosis in fibroblasts [32].…”

Section: Discussionmentioning

confidence: 99%

“…CCN1 also interacts with heparinsulfate-containing proteoglycans (HSPGs), including syndecan 4 and perlecan [31,32]. Integrins and HSPGs are essential for the adhesive and mitogenic function of CCN proteins [31,32], and syndecan 4 and integrin a6b1 are necessary for CCN1-mediated induction of apoptosis in fibroblasts [32]. CCN1 is involved in the inflammatory response by activation of proinflammatory genetic program in murine macrophages throughout a M b 2 and syndecan-4 and is able to directly induce the expression of certain proinflammatory genes, such as TNF-a and IP-10 genes, whereas upregulation of other proinflammatory genes, including IL-1b1 and IL-6, requires the induction of TNF-a as a mediator [33].…”

Section: Discussionmentioning

confidence: 99%

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CCN1 expression in interleukin-6 deficient mouse kidney in experimental model of heart failure

Bonda

Taranta

Kamiński

et al. 2013

Folia Histochem Cytobiol.

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Chronic heart failure often leads to worsening of the renal function. Mediators of this process include inflammatory and neuroendocrine factors. CCN1 (Cyr 61), a member of growth factor-inducible immediate early genes, which modulates inflammation and fibrogenesis, is excreted with urine in the early phase of acute renal injury and may be involved in the pathogenesis of the cardiorenal syndrome. The aim of the study was to evaluate CCN1 protein abundance and localization in the kidney of IL-6-deficient C57BL/6J (IL-6 KO) mice and respective wild-type (WT) animals in basal conditions and in animals with chronic heart failure twelve weeks after myocardial infarction. Age-and sex-matched mice from both strains subjected to sham operation served as controls. One group of WT animals subjected to myocardial infarction was treated with antagonist of AT1 receptor telmisartan over 12 weeks. Abundance and localization of CCN1 protein in kidney were assessed with Western blotting and immunohistochemistry, respectively. In all groups the strongest immunohistochemical reaction for CCN1 was observed in distal convoluted tubules and in smaller arteries, however, the total expression of CCN1 protein was lower in IL-6 KO mice in comparison to WT animals. The main difference in CCN1 distribution between the examined genotypes was lack of reaction in internal renal medulla and very weak reaction in proximal convoluted tubules in IL-6 KO mice. Experimental heart failure only slightly attenuated the expression of CCN1 protein in the kidney of WT mice and had no effect in IL-6 KO mice. Although, blockade of AT1 receptor did not alter CCN1 protein expression in kidneys of WT mice after myocardial infarction, it significantly changed its CCN1 distribution in the renal tubular system. (Folia Histochemica et Cytobiologica 2013, Vol. 51, No. 1, 84-91)

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CCN1 expression in interleukin-6 deficient mouse kidney in experimental model of heart failure

Bonda

Taranta

Kamiński

et al. 2013

Folia Histochem Cytobiol.

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“…CCN4 binds the HSPGs decorin and biglycan (Desnoyers et al, 2001). As discussed below, integrins and HSPGs are essential for the adhesive and mitogenic function of CCN proteins and should be properly considered to be the Journal of Cell Science 119 (23) functional receptors for this family Nishida et al, 2003;Todorovicc et al, 2005). In addition, syndecan 4 and integrin ␣6␤1 are required for CCN1 to induce apoptosis in fibroblasts (Todorovicc et al, 2005).…”

Section: Ccn Receptorsmentioning

confidence: 99%

“…CCN1 and CCN2 also interact with heparan-sulfatecontaining proteoglycans (HSPGs), including syndecan 4 and perlecan, through a heparin-binding domain in module IV Nishida et al, 2003;Todorovicc et al, 2005) (Fig. 3).…”

Section: Ccn Receptorsmentioning

confidence: 99%

All in the CCN family: essential matricellular signaling modulators emerge from the bunker

Leask

Abraham

2006

Journal of Cell Science

603

660

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The CCN family is a group of six secreted proteins that specifically associate with the extracellular matrix. Structurally, CCN proteins are modular, containing up to four distinct functional domains. CCN family members are induced by growth factors and cytokines such as TGFβ and endothelin 1 and cellular stress such as hypoxia, and are overexpressed in pathological conditions that affect connective tissues, including scarring, fibrosis and cancer. Although CCN family members were discovered over a decade ago, the precise biological role, mechanism of action and physiological function of these proteins has remained elusive until recently, when several key mechanistic insights into the CCN family emerged. The CCNs have been shown to have key roles as matricellular proteins, serving as adaptor molecules connecting the cell surface and extracellular matrix (ECM). Although they appear not to have specific high-affinity receptors, they signal through integrins and proteoglycans. Furthermore, in addition to having inherent adhesive abilities that modulate focal adhesions and control cell attachment and migration, they execute their functions by modulating the activity of a variety of different growth factors, such as TGFβ. CCN proteins not only regulate crucial biological processes including cell differentiation, proliferation, adhesion, migration, apoptosis, ECM production, chondrogenesis and angiogenesis, but also have more sinister roles promoting conditions such as fibrogenesis.

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“…Cyr61 is a secreted matrix-associated signaling molecule, which has mainly been associated with promotion of tumor growth, 34 although opposite results also exist. 35 Interestingly, Todorovic et al 36 have reported that Cyr61 induces apoptosis in fibroblasts, in contrast to the promotion of survival in endothelial cells. This kind of cell type-specific response could explain the controversy between some of the previous studies, and make sense of the downregulation of Cyr61 in Amdc fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

Identification of integrins α6 and β7 as c‐Jun‐ and transformation‐relevant genes in highly invasive fibrosarcoma cells

Kielosto

Nummela

Järvinen

et al. 2009

Intl Journal of Cancer

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Understanding the mechanisms of tumor cell invasion is essential for our attempts to prevent cancer deaths. We screened by DNA microarrays the c-Jun-and transformation-related gene expression changes in S-adenosylmethionine decarboxylase (AdoMetDC)-overexpressing mouse fibroblasts that are highly invasive in vivo, and their derivatives expressing a tetracycline-inducible dominant-negative mutant of c-Jun (TAM67) or c-Jun shRNA. Among the small set of target genes detected were integrins a6 and b7, cathepsin L and thymosin b4, all upregulated in the AdoMetDC-transformed cells and downregulated upon reversal of transformation by TAM67 or c-Jun shRNA. The upregulation of integrin a6 subunit, pairing with integrin b1, endowed the transformed cells with the capability to attach to basement membrane laminin and to spread. Further, inhibition of integrin a6 or b1 function with neutralizing antibodies blocked the invasiveness of AdoMetDC-transformants and human HT-1080 fibrosarcoma cells in three-dimensional Matrigel. Moreover, immunohistochemical analyses showed strong integrin a6 staining in high-grade human fibrosarcomas. Our data show that c-Jun can regulate all three key steps of invasion: cell adhesion (integrin a6), basement membrane/extracellular matrix degradation (cathepsin L) and cell migration (thymosin b4). In addition, this is the first study to associate integrin b7, known as a leukocyte-specific integrin binding to endothelial/epithelial cell adhesion molecules, with the transformed phenotype in cells of nonleukocyte origin. As tumor cell invasion is a prerequisite for metastasis, the observed critical role of integrin a6b1 in fibrosarcoma cell invasion/spreading allures testing antagonists to integrin a6b1, alone or combined with inhibitors of cathepsin L and thymosin b4, as chemotherapeutic agents. ' 2009 UICC

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The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts

Cited by 111 publications

References 62 publications

CCN1 expression in interleukin-6 deficient mouse kidney in experimental model of heart failure

CCN1 expression in interleukin-6 deficient mouse kidney in experimental model of heart failure

All in the CCN family: essential matricellular signaling modulators emerge from the bunker

Identification of integrins α6 and β7 as c‐Jun‐ and transformation‐relevant genes in highly invasive fibrosarcoma cells

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