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CYR61 (cysteine-rich, angiogenic inducer, 61)

Written2013-01Chih-Chiun Chen, Lester F Lau
Department of Biochemistry, Molecular Genetics, University of Illinois at Chicago, 900 South Ashland Avenue, Chicago, IL 60607, USA

(Note : for Links provided by Atlas : click)


Alias (NCBI)CCN1
LocusID (NCBI) 3491
Atlas_Id 40256
Location 1p22.3  [Link to chromosome band 1p22]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CYR61 (1p22.3)::COL6A1 (21q22.3)CYR61 (1p22.3)::EPAS1 (2p21)CYR61 (1p22.3)::KCTD15 (19q13.11)
OAS1 (12q24.13)::CYR61 (1p22.3)
Note CYR61 (cysteine-rich angiogenic inducer 61; also named CCN1), first identified as a serum-inducible immediate-early gene, encodes a secreted, extracellular matrix-associated protein that regulates diverse cellular functions (Lau, 2011). CYR61 and five later identified homologs comprise the six-member CCN family, named after the first three members described: CYR61, CTGF (connective tissue growth factor; CCN2), and NOV (nephroblastoma overexpressed; CCN3) (Jun and Lau, 2011). By international consensus, these genes have now been renamed CCN1-6 (Brigstock et al., 2003).


  CYR61 is located on chromosome 1, 86046 kbp ~ 86049 kbp from the p-arm telomere (pter). Each exon is depicted as a box with a unique color, with the numbers of exons shown above. Mature mRNA is ~2,3 kbp in length plus a poly-A tail.
Description Gene structure
The transcribed region of the CYR61 genomic locus spans ~3,2 kb, with 5 exons interspaced by 4 introns. The first exon encodes the 5' untranslated region of the mRNA and followed by sequences encoding the protein secretory signal peptide. The remaining 4 exons each encode a discrete CYR61 domain, and the last exon also contains the mRNA 3' untranslated sequence (O'Brien et al., 1990). The 2 kb DNA upstream of the transcription start site contains sufficient information as the Cyr61 promoter to drive accurate expression in transgenic mice both during embryonic development and in adult wound healing (Latinkic et al., 2001). Since each CYR61 domain is encoded by a discrete exon, it was hypothesized that CYR61 arose through an exon-shuffling mechanism (Brigstock, 1999; Lau and Lam, 1999).

rs3753794 and rs3753793 (r2= 0.77) were associated plasma HDL-cholesterol levels (p= 0.016 and p= 0.008) (Bouchard et al., 2007).
rs954353, located 1,8 kb upstream of CYR61, is linked to susceptibility to colorectal cancer (Fernández-Rozadilla et al., 2010).

Transcription The CYR61 promoter is a TATA-box promoter containing binding sites for many transcription factors including AP1, ATF, E2F, HNF3b, NF1, NFkB, SP1, and SRF, and 2 poly(CA) stretches that may form Z-DNA structure. CYR61 transcription is highly responsive to induction by serum growth factors, cytokines, hormones (angiotensin II, estrogen, vitamin D3), and environmental perturbations including UV irradiation, hypoxia, and mechanical stress. During mouse embryo development Cyr61 is highly expressed in cardiovascular, neuronal, and skeletal systems. In adulthood CYR61 is induced at sites of inflammation and wound repair, and de-regulated in many forms of cancer.
Internal ribosome entry site: CYR61 mRNA contains a highly conserved, guanine-cytosine (GC)-rich region of approximately 200 bp near the 5'-end of the open reading frame which serves as an internal ribosome entry site (Mukudai et al., 2010). It may facilitate CYR61 production in stressful conditions such as during viral infection (Johannes et al., 1999).
Alternative splicing: hypoxia during breast carcinogenesis may promote a shift of CYR61 alternative splicing to promote CYR61 production. In normal breast tissue most CYR61 RNA transcript contains intron-3, which does not produce CYR61 protein. In cancerous tissues that often suffer hypoxia, intron-3 is spliced out, resulting in mature CYR61 mRNA and a higher level of CYR61 production (Hirschfeld et al., 2009; Hirschfeld et al., 2011).
3'-UTR: CYR61 3'UTR contains 5 copies of AU-rich element (ARE) in the 3'-UTR, which causes RNA instability (Leng et al., 2002). In addition, CYR61 mRNA 3'-UTR contains a microRNA-155 target site. In preeclampsia where placental miR-155 level is high, CYR61 mRNA is reduced due to targeted degradation by miR-155 (Zhang et al., 2010).
Pseudogene None identified yet.


Note CYR61 is a secreted protein located in the extracellular matrix and on cell surface (Yang and Lau, 1991), and regulates diverse cellular activity including cell adhesion, migration, proliferation, apoptosis, senescence, and differentiation (Lau, 2011). It binds to and acts through cell surface integrin receptors, with heparan sulfate proteoglycans (HSPGs) as coreceptors in some contexts (Chen and Lau, 2009; Lau, 2011). Cell adhesion to CYR61 as a substrate induces activation of various signaling molecules including Rac1, FAK, the MAP kinases ERK1/ERK2, and transcription factors such as NFκB (Chen et al., 2001a; Bai et al., 2010). CYR61 is a strong inducer of intracellular reactive oxygen species (ROS) through multiple cellular sources including NADPH Oxidase, 5-lipoxygenase, sphingomyelinase, and the mitochondria; accumulation of ROS mediates Cyr61-promoted apoptosis and cellular senescence (Chen CC et al., 2007; Jun and Lau, 2010b; Juric et al., 2012).
Targeted Cyr61 deletion in mice is embryonic lethal due to cardiac atrioventricular septal defects, impaired placentation, and compromised blood vessel integrity (Mo et al., 2002; Mo and Lau, 2006). Consistently, CYR61 induces pro-angiogenic activity in endothelial cells in culture and neovascularization in vivo (Babic et al., 1998; Fataccioli et al., 2002; Leu et al., 2002).
In adulthood Cyr61 expression is strongly associated with inflammation and wound repair (Lau, 2011). In particular, Cyr61 plays a critical role in the resolution of fibrosis during wound healing by inducing cellular senescence in myofibroblasts (Jun and Lau, 2010b). In inflammation, CYR61 is critical for TNFα-mediated apoptosis in vivo, and can enhance the cytotoxicity of other TNF family cytokines including LTα, FasL, and TRAIL (Chen CC et al., 2007; Franzen et al., 2009; Juric et al., 2009). Finally, CYR61 expression is de-regulated in most human chronic inflammatory diseases including rheumatoid arthritis, diabetic retinopathy and nephropathy, atherosclerosis, and many cancers (Lau, 2011).
  Each domain is depicted as a box with a unique color, with the domain name shown in the box. The grey box represents the secretory signal peptide. Integrin/HSPGs binding sites are marked as stripes.
Description Domain structure, receptor binding sites, and interacting proteins
Full-length CYR61 precursor is 381 amino acids in length, with aa 1-24 being the secretory signal peptide. The calculated molecular size for mature CYR61 is 39,4 kDa, and on SDS-PAGE it migrates as a ~40 kDa protein band. CYR61 contains unusually high cysteine content (37 cysteines in the processed protein), in addition, all cysteines are completely conserved among CCN1, CCN2, CCN3, and CCN4.
CYR61 is a direct ligand of several integrin receptors, including αvβ3, αvβ5, αIIbβ3, αMβ2, and α6β1, and has strong binding for cell surface HSPGs (Kireeva et al., 1998; Jedsadayanmata et al., 1999; Chen et al., 2000; Grzeszkiewicz et al., 2002; Schober et al., 2002). Cyr61 binds preferentially to particular integrins in a cell-type specific manner, and this interaction mediates many activities of CYR61.
Proteins of the CCN protein family consists of four structural domains (Holbourn et al., 2008). The first CYR61 domain has sequence homologies to insulin-like growth factor binding protein (IGFBP), although CYR61 does not bind IGFs. The second domain is homologous to the von Willebrand Factor type C repeat (vWC). It has a functional integrin αvβ3 binding site with the sequence NCKHQCTCIDGAVGCIPLCP from aa 116 to 135 (Chen et al., 2004). A point mutation substituting the center aspartic acid residue to alanine (D125A mutation) eliminates the binding activity. Consistent with the notion that CYR61 induces angiogenesis through direct binding to integrin αvβ3, the D125A mutation in Cyr61 effectively abrogates its angiogenic activity (Chen et al., 2004).
Following the vWC-domain is a hinge-region that does not seem to have a particular 3d structure, and its aa sequence is not conserved among the CCN-family members.
The third domain has homology to thrombospondin type 1 repeat (TSR). It contains an integrin α6β1 binding site called T1 with the sequence TTSWSQCSKS from aa 231-240 (Leu et al., 2003).
The fourth domain (CT) has homology to the cysteine-knot motif, and has two binding sites to integrin α6β1 and HSPGs called H1 (aa 278-295, YSSLKKGKKCSKTKKSPE) and H2 (aa 302-314, SSVKKYRPKYCGS), each contributes to heparin binding and integrin α6β1/HSPGs-mediated fibroblast cell adhesion (Chen et al., 2000). The H2 site also overlaps a binding site for integrin αMβ2 and can mediate monocyte cell adhesion (Schober et al., 2002).
The domains of CYR61 may function independently. A mutant CYR61 protein with the CT-domain deleted is unable to induce fibroblast cell adhesion, but still able to activate αv integrin-mediated activities, including cell migration, and potentiate bFGF-induced cell proliferation (Grzeszkiewicz et al., 2001). Similarly, a CYR61 mutant protein (DM) with disrupted integrin α6β1/HSPGs-binding sites is defective for CYR61 supported fibroblast functions, but can still promoting αv integrin-mediated angiogenic activities (Chen et al., 2004). The N-terminal half of CYR61 alone, which contains domains 1 and 2, can bind purified integrin αvβ3 and mediate endothelial cell adhesion (Chen et al., 2004). Mixing CYR61-D125A (mutated in the αv integrin binding site), with CYR61-DM (mutated in the α6β1/HSPG binding sites) can reconstitute wild-type CYR61 function to synergize with TNFα and induce fibroblast apoptosis (Chen CC et al., 2007).


Germinal The CYR61 gene is located in human chromosome 1p22.3, within the region of a susceptibility gene locus for atrioventricular septal defects (AVSD; 1p21-1p31) (Sheffield et al., 1997). Targeted disruption of Cyr61 in mice results in severe atrioventricular septal defects (AVSD). Furthermore, Cyr61 haploinsufficiency results in delayed formation of the ventricular septa in embryos and persistent ostium primum atrial septal defects (ASD) in ≈20% of adults (Mo and Lau, 2006).

Implicated in

Entity Cancer
Note CYR61 expression is regulated by a wide array of growth factors, inflammatory cytokines, and hormones, which are often de-regulated in cancerous tissues. CYR61 protein is a potent context-dependent regulator of many cellular functions important in tumorigenesis, including cell proliferation, survival/apoptosis, senescence, motility/chemotaxis, invasion in extracellular matrix, gene expression, differentiation, and angiogenesis. Perhaps as a consequence CYR61 is aberrantly expressed in most forms of solid tumors where, depending on cancer types, it may have either promoting or suppressing roles. Many research works are ongoing to understand CYR61 function in the context of each specific type of cancer, which may in the future lead to better prognostic tools and cancer treatment.
Entity Breast cancer
Note CYR61 may have a role in breast cancer progression and the development of resistance to anti-cancer drugs. CYR61 expression is associated with more advanced cancer features, including tumor stage, size, lymph node infiltration, age, and estrogen receptor expression (Xie et al., 2001). Over-expressing CYR61 in the breast cancer cell line MCF-7 can induce estrogen-independent cell growth, and promote tumorigenesity in nude mice (Tsai et al., 2002). CYR61 over-expression confers cellular resistance to apoptosis induction by anti-cancer drugs including Taxol, Adriamycin, and β-lapachone (Lin et al., 2004; Menendez et al., 2005). In addition, CYR61 induction by the Hippo-LATS signaling pathway enables Taxol resistance in breast cancer cells (Lai et al., 2011). These results suggest CYR61 may be a novel therapeutic target in treating drug-resistant breast cancers.
Entity Endometrial cancer
Note CYR61 expression in endometrial cancers is down-regulated when compared to matched normal endometrial tissue, suggesting it may have a tumor-suppressing role (Chien et al., 2004). Consistent with the idea, over-expressing CYR61 in the endometrial cancer cell line AN3CA decreased cell growth in vitro, and abrogated tumorigenicity in nude mice (Chien et al., 2004). Moderate to high CYR61 levels are detectable by immunohistochemical analysis in ~50% of endometrioid adenocarcinoma, the most common form of endometrial cancer. However its expression is not associated with pathological features including age, cancer stage, invasion to surrounding tissues, or lymph node metastasis (Watari et al., 2009).
Entity Ovarian cancer
Note CYR61 mRNA in ovarian cancer tissues is up-regulated in ~60% patients with a range from 2 to 10 fold higher than that found in normal ovary samples. Its over-expression is also associated with higher disease stages (Gery et al., 2005). In ovarian cancer cell lines, CYR61 promotes cell proliferation, enhances tumor growth in nude mice, and confers resistance to cytotoxicity by the anti-cancer drug carboplatin (Gery et al., 2005). These results suggest that CYR61 may have a promoting role in ovarian cancer.
Entity Prostate cancer
Note CYR61 may promote primary prostate cancer in situ but repress the spreading of prostate cancer cells after surgical removal of the primary tumor. Its expression is up-regulated in benign prostate hyperplasia compared to normal prostate tissues (Sakamoto et al., 2004), and higher in prostate cancer than in normal (D'Antonio et al., 2010b) and benign hyperplasia tissues (Lv et al., 2009). In addition, CYR61 supports cell adhesion and proliferation in prostate epithelial and cancer cells (Franzen et al., 2009; Sakamoto et al., 2004). Together these results show CYR61 may have a promoting role in prostate cancer. However, higher CYR61 expression is associated with >50% reduced cancer recurrence rates in patients after radical prostatectomy for clinically localized prostate cancer (D'Antonio et al., 2010a). In addition CYR61 can cooperate with TRAIL to induce prostate cancer cell apoptosis (Franzen et al., 2009). It is hypothesized that CYR61 may function in a TRAIL-dependent immune surveillance mechanism to repress potential prostate cancer cell spreading in the hosts leading to reduced cancer recurrence.
Entity Lung cancer
Note CYR61 acts as a tumor-suppressor in lung cancers. Its mRNA level in lung tumor is decreased compared to adjacent non-cancerous tissues, and more reduced expression is associated with more advanced disease and poorer patient survival rates (Chen PP et al., 2007; Mori et al., 2007). Stable ectopic expression of CYR61 in non-small cell lung carcinoma cell lines caused cell cycle arrests in G1, elevated p53 and p21 expression, and reduced tumorigenecity in nude mice (Tong et al., 2001).
Entity Osteosarcoma
Note Immunohistochemical analysis of osteosarcoma tissue microarrays using anti-CYR61 antibodies shows that higher CYR61 levels are associated with higher tumor grades and shorter patient survival (Sabile et al., 2012; Fromigue et al., 2011). Over-expressing CYR61 in osteosarcoma cell lines enhanced tumorigenecity and lung metastasis in nude mice (Sabile et al., 2012), while silencing CYR61 abrogated cell Matrigel invasion in vitro, and lung metastasis in vivo (Fromigue et al., 2011). These results suggest that CYR61 may promote osteosarcoma tumorigenesis and metastasis.
Entity Pancreatic cancer
Note Elevated CYR61 in pancreatic ductal adenocarcinoma compared to adjacent normal tissue was detected in patient tissue samples by in situ hybridization and immunihistochemical analysis (Haque et al., 2012; Haque et al., 2011). In a human pancreatic cancer cell line Panc-1, CYR61 expression is necessary for cellular expression of stem cell-like phenotype and cell migration, and tumorigenesis in nude mice (Haque et al., 2011). CYR61 may act by binding integrin alphavbeta3 to suppress cellular Notch-1 proteosome degradation, leading to the activation of Sonic Hedgehog signaling and cell migration (Haque et al., 2012).
Entity Glioma
Note CYR61 has promoting roles in glioma tumorigenesis. Its mRNA and protein levels are elevated compared to normal brain tissues, and in addition, its aberrant expression is associated with higher cancer grades and poor prognosis (Xie et al., 2004a; Goodwin et al., 2010). Over-expressing CYR61 in glioma cells in vitro activates ILK, Akt, and GSK3/b-catenin signaling, and promotes pro-tumorigenic cellular activities including proliferation, colony-formation in soft agar, and cell migration. Forced CYR61 expression in glioma cells enhanced tumorigenicity when xenografted in nude mice (Xie et al., 2004a), while injecting CYR61 siRNA in pre-established tumor xenografts reduced cell proliferation and tumor growth (Goodwin et al., 2010).
Entity Colorectal cancer
Note CYR61 mRNA levels are ~10-fold higher in colorectal cancers compared to that in normal colon tissues. However expression is reduced in more advanced cancers and there is no statistically significant association between CYR61 and pathological parameters (Ladwa et al., 2011).
Entity Wound healing and fibrogenesis
Note CYR61 expression is highly induced during injury/repair of many tissue and organs, including in the granulation tissue of skin wounds (Chen et al., 2001b; Rittié et al., 2011), liver after partial hepatectomy (Su et al., 2002), the callus in the healing bone (Hadjiargyrou et al., 2000; Lienau et al., 2006), and the heart after myocardial infarction (Hilfiker-Kleiner et al., 2004).
Tissue wound repair in mammals occurs in three distinct but overlapping phases: inflammation, followed by formation of granulation tissues (fibroblasts activation, proliferation, fibrogenesis, and angiogenesis), and finally remodeling and resolution of the granulation tissue to form the mature tissue (Gurtner et al., 2008). Resident fibroblasts and recruited fibrocytes are activated in wounds to proliferate and become myofibroblasts, which rapidly synthesize extracellular matrix. The matrix is important for maintaining tissue integrity and may help parenchymal cell regeneration. CYR61 is highly expressed in the granulation tissue during the resolution phase in skin wounds, where CYR61 drives fibrogenic myofibroblasts to become senescent cells. Senescent myofibroblasts cease to proliferate and express an anti-fibrotic phenotype, including the enhanced expression of matrix degradation enzymes to help resolution of fibrosis (Rodier and Campisi, 2011; Jun and Lau, 2010b; Jun and Lau, 2010a).
Entity Diabetic retinopathy and nephropathy
Note Cyr61 may contribute to diabetic retinopathy. Its expression is induced by advanced glycation end products (Hughes et al., 2007). In proliferative diabetic retinal membrane CYR61 is induced in ganglion cells, endothelial cells, and smooth muscle cells, where it may contribute to the loss of normal capillary pericytes by apoptosis (Liu et al., 2008) and enhancement of aberrant neovascularization (Zhang et al., 2012). Elevated CYR61 in vitreous is detected in patients with proliferative diabetic retinopathy (You et al., 2012). In the normal adult kidney CYR61 is expressed by podocytes and tubular epithelial cells, where CYR61 may function to maintain normal podocyte differentiation, but suppress mesangial cell adhesion and migration (Sawai et al., 2007). Podocyte expression of Cyr61 is diminished in patients with diabetic nephropathy, and this may be associated with mesangial expansion in glomerulopathies (Sawai et al., 2007).
Entity Vascular disease
Note CYR61 is induced in human arteriosclerotic lesions (Hilfiker et al., 2002) and inflammatory cardiomyopathy (Rother et al., 2010).
Entity Inflammatory diseases
Note CYR61 is highly expressed in rheumatoid arthritis (Zhang et al., 2009) as well as in patients with Crohn's disease or ulcerative colitis (Koon et al., 2008).


CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth.
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This paper should be referenced as such :
Chen, CC ; Lau, LF
CYR61 (cysteine-rich, angiogenic inducer, 61)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(7):445-452.
Free journal version : [ pdf ]   [ DOI ]

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RefSeq transcript (Entrez)
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