The CCN family of genes: a perspective on CCN biology and therapeutic potential.

Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, Canada, .
Journal of Cell Communication and Signaling 12/2008; 1(3-4):159-64. DOI: 10.1007/s12079-008-0022-6
Source: PubMed

ABSTRACT The CCN family of genes currently comprises six secreted proteins (designated CCN1-6 after Cyr61/CCN1; ctgf/CCN2; Nov/CCN3; WISP1/CCN4; WISP2/CCN5, WISP3/CCN6) with a similar mosaic primary structure. It is now well accepted that CCN proteins are not growth factors but matricellular proteins that modify signaling of other molecules, in particular those associated with the extracellular matrix. CCN proteins are involved in mitosis, adhesion, apoptosis, extracellular matrix production, growth arrest and migration of multiple cell types. Since their first identification as matricellular factors, the CCN proteins now figure prominently in a variety of major diseases and are now considered valid candidates for therapeutic targeting. Dissection of the molecular mechanisms governing the biological properties of these proteins is being actively pursued by an expanding network of scientists around the globe who will meet this year at the 5th International Workshop on the CCN family of Genes, organized by the International CCN Society ( ), home for an international cadre of collaborators working in the CCN field.

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    • "Three additional Wnt-inducible secreted proteins were later identified (CCN4, CCN5, CCN6). Early studies suggested that these proteins were bona-fide growth factors; however data now supports the role of CCN proteins as matricellular proteins that can bind to matrix and modulate cellular functions (Leask and Abraham, 2006; Yeger and Perbal, 2007; Chen and Lau, 2009) via the modification of signals from other molecules such as transforming growth factor beta (TGFβ). Evidence proposes that CTGF is strongly associated with fibrosis (Brigstock, 2009), that CTGF is a TGFβ inducible gene, and CTGF is significantly up-regulated in experimental models of fibrosis associated with aberrant ECM deposition (Ito et al., 1998; Lasky et al., 1998; Gupta et al., 2000; Sato et al., 2000; Lang et al., 2008). "
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    ABSTRACT: Glaucoma is an optic neuropathy affecting approximately 60 million people worldwide and is the second most common cause of irreversible blindness. Elevated intraocular pressure (IOP) is the main risk factor for developing glaucoma and is caused by impaired aqueous humor drainage through the trabecular meshwork (TM) and Schlemm's canal (SC). In primary open angle glaucoma (POAG), this elevation in IOP in turn leads to deformation at the optic nerve head (ONH) specifically at the lamina cribrosa (LC) region where there is also a deposition of extracellular matrix (ECM) molecules such as collagen and fibronectin. Matricellular proteins are non-structural secreted glycoproteins that help cells communicate with their surrounding ECM. This family of proteins includes connective tissue growth factor (CTGF), also known as CCN2, thrombospondins (TSPs), secreted protein acidic and rich in cysteine (SPARC), periostin, osteonectin, and Tenascin-C and -X and other ECM proteins. All members appear to play a role in fibrosis and increased ECM deposition. Most are widely expressed in tissues particularly in the TM and ONH and deficiency of TSP1 and SPARC have been shown to lower IOP in mouse models of glaucoma through enhanced outflow facility. The role of these proteins in glaucoma is emerging as some have an association with the pathophysiology of the TM and LC regions and might therefore be potential targets for therapeutic intervention in glaucoma.
    Matrix Biology 07/2014; 37. DOI:10.1016/j.matbio.2014.03.007 · 3.65 Impact Factor
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    • "Connective tissue growth factor ( CTGF , CCN2 ) CCN2 is a prototypical member of the CCN ( cyr61 , ctgf and nov ) family of matricellular proteins ( Leask and Abraham 2004 ; Yeger and Perbal 2007 ) . It has long been appreciated that CCN2 is an excellent surrogate marker for the severity of fibrosis including that of SSc ( Moussad and Brigstock 2000 ; Leask et al . "
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    ABSTRACT: There are no approved drugs for treating the fibrosis in scleroderma (systemic sclerosis, SSc). Myfibroblasts within connective tissue express the highly contractile protein α-smooth muscle actin (α-SMA) and are responsible for the excessive synthesis and remodeling of extracellular matrix (ECM) characterizing SSc. Drugs targeting myofibroblast differentiation, recruitment and activity are currently under consideration as anti-fibrotic treatments in SSc but thus far have principally focused on the transforming growth factor β (TGFβ), endothelin-1 (ET-1), connective tissue growth factor (CCN2/CTGF) and platelet derived growth factor (PDGF) pathways, which display substantial signaling crosstalk. Moreover, peroxisome proliferator-activated receptor (PPAR)γ also appears to act by intervening in TGFβ signaling. This review discusses these potential candidates for antifibrotic therapy in SSc.
    Journal of Cell Communication and Signaling 06/2011; 5(2):125-9. DOI:10.1007/s12079-011-0122-6
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    • "The CCN (Cyr61/Connective tissue growth factor/Nephroblastoma-overexpressed) family is made up of six core members including Cyr61/CCN1, CTGF/CCN2, NOV/CCN3, WISP1/ CCN4, WISP2/CCN5 and WISP3/CCN6 (Perbal, 2001b; Perbal, 2008b). CCN proteins are secreted, matrix-associated proteins that have important roles in regulating diverse biological functions, including proliferation, differentiation, angiogenesis, survival, adhesion and motility (Perbal, 2001a; Yeger and Perbal, 2007; Holbourn et al., 2008). Specific CCN receptors have yet to be identified; however, several studies have indicated CCN proteins bind to cell surface integrins and modulate integrin-mediated pathways (Lau and Lam, 1999; Leu et al., 2002; Leu et al., 2003; Lin et al., 2005; Vallacchi et al., 2008; Katsube et al., 2009). "
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    ABSTRACT: The CCN (Cy61, CTGF and NOV) family of proteins is a group of matricellular biomolecules involved in both physiological and pathological processes. Elevated expression of the CCN3 (also known as NOV, Nephroblastoma overexpressed) gene has been detected in clinical samples of the skeletal muscle cancer rhabdomyosarcoma, with the highest expression found in the alveolar subtype (aRMS). Over 80% of aRMSs are characterized by a chromosomal translocation-derived fusion transcription factor PAX3-FKHR. In this study, we linked elevated CCN3 levels in aRMS cells to PAX3-FKHR expression. We found reduced CCN3 levels in aRMS cells following small interfering RNA knockdown of PAX3-FKHR, and increased CCN3 levels in C2 myoblasts following ectopic expression of PAX3-FKHR. Promoter, electrophoretic mobility shift assay and chromatin immunoprecipitation analyses confirmed that the CCN3 gene was a direct target for PAX3-FKHR transcriptional activation through a paired-domain DNA sequence in the first intron of the CCN3 gene. To determine the function of CCN3, we showed that knockdown and ectopic expression of CCN3 decreased survival and increased differentiation in aRMS cells, respectively. In addition, we found that exogenously supplied CCN3 protein promoted aRMS cell adhesion, migration and Matrigel invasion. Taken together, data from this study have (1) provided a mechanistic basis for the CCN3 overexpression in aRMS cells, and (2) identified CCN3 as an autocrine/paracrine factor that contributes to the aggressive behavior of aRMS cells, perhaps through a positive feedback loop. Thus, CCN3 may be an attractive target for therapeutic intervention in aRMS.
    Oncogene 03/2011; 30(32):3549-62. DOI:10.1038/onc.2011.69 · 8.56 Impact Factor
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