Alternative titles; symbols
HGNC Approved Gene Symbol: CCN1
Cytogenetic location: 1p22.3 Genomic coordinates (GRCh38): 1:85,580,761-85,583,950 (from NCBI)
CYR61 is a secreted, cysteine-rich, heparin-binding protein encoded by a growth factor-inducible immediate-early gene. Acting as an extracellular, matrix-associated signaling molecule, CYR61 promotes the adhesion of endothelial cells through interaction with integrin and augments growth factor-induced DNA synthesis in the same cell type (summary by Babic et al., 1998).
The transcription of immediate-early genes is induced rapidly when cells are stimulated by growth factors or transforming oncogenes. See NOV (164958). Cyr61 is a mouse immediate-early gene, and Jay et al. (1997) identified the human homolog in an embryonic cDNA library. The human CYR61 gene encodes a predicted 382-amino acid protein that is 93% identical to the mouse protein, and contains 10% cysteine residues and a 24-amino acid N-terminal signal sequence. Northern blot analysis revealed 2.5-kb and minor 4-kb CYR61 mRNAs that are expressed widely at varying levels.
By Western blot analysis following protein overexpression in liver, Rother et al. (2010) found that full-length mouse Ccn1 was expressed as glycosylated and unglycosylated forms with apparent molecular masses of 42 to 50 kD. A 21-kD plasmin (173350) degradation fragment of Ccn1 was also released into the circulation.
Babic et al. (1998) showed that purified CYR61 stimulates directed migration of human microvascular endothelial cells in culture through the alpha(V)beta(3)-dependent pathway and induces neovascularization in rat corneas. Both the chemotactic and angiogenic activities of CYR61 can be blocked by specific anti-CYR61 antibodies. Whereas most human tumor-derived cell lines tested expressed CYR61, a gastric adenocarcinoma cell line did not. Expression of the CYR61 cDNA under the regulation of a constitutive promoter from this gastric cancer cell line significantly enhanced the tumorigenicity of these cells as measured by growth in immunodeficient mice, resulting in tumors that were larger and more vascularized than those produced by control cells. Taken together, these results identified CYR61 as an angiogenic inducer that can promote tumor growth and vascularization; the results also suggested to Babic et al. (1998) potential roles for CYR61 in physiologic and pathologic neovascularization.
By functional and biochemical analysis, Kireeva et al. (1998) determined that adhesion of human umbilical vein endothelial cells to CYR61 requires divalent cations and is inhibited by RGD-containing peptides and by anti-alpha(V)beta(3) antibody under both serum-free and serum-containing conditions. Binding analysis showed that purified CYR61 and alpha(V)beta(3) specifically interact with one another.
Kim et al. (1997) noted that Cyr61 and the products of the other immediate-early genes, CTGF (121009) and NOV, have significant sequence homology to the insulin-like growth factor binding proteins (IGFBPs) and contain the conserved N-terminal IGFBP motif (see IGFBP7, 602867). They proposed that, together with IGFBP7, these proteins constitute a subfamily of IGFBPs that bind insulin-like growth factors with low affinity. Martinerie et al. (1997) stated that CTGF, NOV, and Cyr61 also contain a von Willebrand factor (613160) type C repeat, thought to be involved in oligomerization; a thrombospondin I (188060) repeat module that may mediate interaction with extracellular matrix molecules; and a putative dimerization CT motif.
Using cDNA array hybridization, Chen et al. (2001) identified genes regulated by CYR61 in primary human skin fibroblasts. The CYR61-regulated genes fell into several groups that participate in cutaneous wound healing, including angiogenesis and lymphogenesis, inflammation, extracellular matrix remodeling, and cell-matrix interactions. CYR61-mediated gene expression required the heparin-binding activity of CYR61, cellular de novo transcription, and protein synthesis, and was largely dependent on the activation of MAPKs p42 (176948) and p44 (601795). Chen et al. (2001) demonstrated induction of CYR61 in dermal fibroblasts of granulation tissue during cutaneous wound repair. They concluded that induction of CYR61 with wounding activates a genetic program for wound repair in skin fibroblasts.
By mutation analysis, Grzeszkiewicz et al. (2001) determined that the C-terminal domain of CYR61, which resembles the cysteine knots found in some growth factors, is required to support adhesion of primary human skin fibroblasts, but is not required to stimulate chemotaxis or to enhance basic fibroblast growth factor (FGFB; 134920)-induced mitogenesis. They concluded that CYR61 interacts with different integrin subunits to specifically promote adhesion, migration, and mitogenesis in primary human fibroblasts.
Sampath et al. (2001) used rapid analysis of differential expression (RADE) to identify genes that are abnormally expressed in leiomyomas. Of the several genes identified, CYR61, a member of the CCN family of growth and angiogenic regulators, was shown to be markedly downregulated at the mRNA and protein levels in leiomyoma tumors compared with the 38 matched uterine myometrial controls. In addition, in situ hybridization experiments corroborated the lack of CYR61 expression in leiomyoma cells, whereas abundant transcript levels were identified in adjacent myometrial smooth muscle cells. To elucidate the mechanisms of CYR61 gene regulation in leiomyomas, they determined the effects of ovarian steroids, FGFB, and serum on CYR61 expression using an ex vivo culture system. Treatment of human myometrial explants with 17-beta-estradiol and FGFB upregulated CYR61 transcripts. Paradoxically, neither 17-beta-estradiol nor FGFB was capable of upregulating CYR61 mRNA in leiomyoma explants despite elevated levels of ESRA (133430) mRNA. The authors concluded that dysregulation of CYR61 by estrogen and FGFB may contribute to downregulation of CYR61 in leiomyomas which, in turn, may predispose uterine smooth muscle cells toward sustained growth.
Tong et al. (2001) found that expression of CYR61 mRNA was decreased markedly in 4 of 5 human nonsmall cell lung cancers (NSCLCs). Transfection of CYR61 into 2 NSCLC cell lines that do not express endogenous CYR61 resulted in decreased proliferation, and they formed 60 to 90% fewer colonies in a colony formation assay. Cell cycle analysis revealed that both cell lines developed G1 arrest after transfection, with upregulated expression of p53 (191170), p21-WAF1 (116899), and pocket protein RB2/p130 (180203), and decreased activity of cyclin-dependent kinase-2 (116953).
Using adenovirus-mediated gene transfer, Rother et al. (2010) found that overexpression of mouse Ccn1 in liver significantly reduced cardiac disease and immune cell infiltration in murine experimental autoimmune myocarditis, a model of human inflammatory cardiomyopathy. In vivo tracking revealed that epitope-tagged Ccn1 bound to spleen macrophages, but not to cardiomyocytes. Ccn1 did not alter cardiac chemokine and cytokine expression, but it strongly inhibited migration of spleen macrophages and lymphocytes in vitro. Preincubation with Ccn1 diminished migration of human primary monocytes and THP-1 monocytic cells and abrogated their chemotactic response to MCP1 (CCL2; 158105), MIP1-alpha (CCL3; 182283), and SDF1-alpha (CXCL12; 600835).
Jay et al. (1997) mapped the human CYR61 gene to 1p31-p22 by fluorescence in situ hybridization. By analysis of somatic cell hybrids and fluorescence in situ hybridization, Martinerie et al. (1997) refined the map position to 1p22.3.
Mo et al. (2002) disrupted the Cyr61 gene in mice and found that Cyr61-null mice suffered embryonic death. About 30% succumbed to a failure in chorioallantoic fusion, and the remainder perished due to placenta vascular insufficiency and compromised vessel integrity. There was a specific defect in vessel bifurcation at the chorioallantoic junction that led to undervascularization of the placenta. The mutant phenotype was correlated with impaired Vegfc (601528) expression in the allantoic mesoderm, suggesting that CYR61-regulated expression of VEGFC plays a role in vessel bifurcation.
Babic, A. M., Kireeva, M. L., Kolesnikova, T. V., Lau, L. F. CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. Proc. Nat. Acad. Sci. 95: 6355-6360, 1998. [PubMed: 9600969] [Full Text: https://doi.org/10.1073/pnas.95.11.6355]
Chen, C.-C., Mo, F.-E., Lau, L. F. The angiogenic factor Cyr61 activates a genetic program for wound healing in human skin fibroblasts. J. Biol. Chem. 276: 47329-47337, 2001. [PubMed: 11584015] [Full Text: https://doi.org/10.1074/jbc.M107666200]
Grzeszkiewicz, T. M., Kirschling, D. J., Chen, N., Lau, L. F. CYR61 stimulates human skin fibroblast migration through integrin alpha-V-beta-5 and enhances mitogenesis through integrin alpha-V-beta-3, independent of its carboxyl-terminal domain. J. Biol. Chem. 276: 21943-21950, 2001. [PubMed: 11287419] [Full Text: https://doi.org/10.1074/jbc.M100978200]
Jay, P., Berge-Lefranc, J. L., Marsollier, C., Mejean, C., Taviaux, S., Berta, P. The human growth factor-inducible immediate early gene, CYR61, maps to chromosome 1p. Oncogene 14: 1753-1757, 1997. [PubMed: 9135077] [Full Text: https://doi.org/10.1038/sj.onc.1200986]
Kim, H.-S., Nagalla, S. R., Oh, Y., Wilson, E., Roberts, C. T., Jr., Rosenfeld, R. G. Identification of a family of low-affinity insulin-like growth factor binding proteins (IGFBPs): characterization of connective tissue growth factor as a member of the IGFBP superfamily. Proc. Nat. Acad. Sci. 94: 12981-12986, 1997. [PubMed: 9371786] [Full Text: https://doi.org/10.1073/pnas.94.24.12981]
Kireeva, M. L., Lam, S. C.-T., Lau, L. F. Adhesion of human umbilical vein endothelial cells to the immediate-early gene product Cyr61 is mediated through integrin alpha(V)beta(3). J. Biol. Chem. 273: 3090-3096, 1998. [PubMed: 9446626] [Full Text: https://doi.org/10.1074/jbc.273.5.3090]
Martinerie, C., Viegas-Pequignot, E., Nguyen, V. C., Perbal, B. Chromosomal mapping and expression of the human cyr61 gene in tumour cells from the nervous system. J. Clin. Path. 50: 310-316, 1997. [PubMed: 9215147] [Full Text: https://doi.org/10.1136/jcp.50.4.310]
Mo, F.-E., Muntean, A. G., Chen, C.-C., Stolz, D. B., Watkins, S. C., Lau, L. F. CYR61 (CCN1) is essential for placental development and vascular integrity. Molec. Cell. Biol. 22: 8709-8720, 2002. [PubMed: 12446788] [Full Text: https://doi.org/10.1128/MCB.22.24.8709-8720.2002]
Rother, M., Krohn, S., Kania, G., Vanhoutte, D., Eisenreich, A., Wang, X., Westermann, D., Savvatis, K., Dannemann, N., Skurk, C., Hilfiker-Kleiner, D., Cathomen, T., Fechner, H., Rauch, U., Schultheiss, H.-P., Heymans, S., Eriksson, U., Scheibenbogen, C., Poller, W. Matricellular signaling molecule CCN1 attenutates experimental autoimmune myocarditis by acting as a novel immune cell migration modulator. Circulation 122: 2688-2698, 2010. [PubMed: 21135363] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.110.945261]
Sampath, D., Zhu, Y., Winneker, R. C., Zhang, Z. Aberrant expression of Cyr61, a member of the CCN (CTGF/Cyr61/Cef10/NOVH) family, and dysregulation by 17-beta-estradiol and basic fibroblast growth factor in human uterine leiomyomas. J. Clin. Endocr. Metab. 86: 1707-1715, 2001. [PubMed: 11297607] [Full Text: https://doi.org/10.1210/jcem.86.4.7423]
Tong, X., Xie, D., O'Kelly, J., Miller, C. W., Muller-Tidow, C., Koeffler, H. P. Cyr61, a member of CCN family, is a tumor suppressor in non-small cell lung cancer. J. Biol. Chem. 276: 47709-47714, 2001. [PubMed: 11598125] [Full Text: https://doi.org/10.1074/jbc.M107878200]