Biology:CYR61

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Cysteine-rich angiogenic inducer 61 (CYR61) or CCN family member 1 (CCN1), is a matricellular protein that in humans is encoded by the CYR61 gene.[1]

CYR61 is a secreted, extracellular matrix (ECM)-associated signaling protein of the CCN family (CCN intercellular signaling protein).[2][3] CYR61 is capable of regulating a broad range of cellular activities, including cell adhesion, migration, proliferation, differentiation, apoptosis, and senescence through interaction with cell surface integrin receptors and heparan sulfate proteoglycans. During embryonic development, CYR61 is critical for cardiac septal morphogenesis, blood vessel formation in placenta, and vascular integrity. In adulthood CYR61 plays important roles in inflammation and tissue repair, and is associated with diseases related to chronic inflammation, including rheumatoid arthritis, atherosclerosis, diabetes-related nephropathy and retinopathy, and many different forms of cancers.

CCN protein family

CYR61 was first identified as a protein encoded by a serum-inducible gene in mouse fibroblasts.[2][4] Other highly conserved homologs were later identified to comprise the CCN protein family (CCN intercellular signaling protein).[5][6][7] The CCN acronym is derived from the first three members of the family identified, namely CYR61 (CCN1), CTGF (connective tissue growth factor, or CCN2), and NOV (nephroblastoma overexpressed, or CCN3). These proteins, together with WISP1 (CCN4), WISP2 (CCN5), and WISP3 (CCN6) comprise the six members of the family in vertebrates and have been renamed CCN1-6 in order of their discovery by international consensus.[8] CCN proteins function as matricellular proteins, which are extracellular matrix proteins that play regulatory roles, particularly in the context of wound repair.[9]

Gene structure and regulation

CYR61 is located at human chromosome 1p22.3, whereas the mouse Cyr61 gene is located at chromosome 3, 72.9cM.[10] The mouse CYR61 coding region spans ~3.2 Kb, containing 5 exons interspaced with 4 introns.[11] The first exon encodes 5’-UTR sequence and the first several amino acids in the secretory signal peptide. The remaining four exons each encode a distinct CCN1 domain. The 5th exon also contains the 3’-UTR sequences, which has 5 copies of AU-rich elements that confers a short mRNA half life, and a mir-155 target site.[12] The CYR61 promoter is a TATA box containing promoter, with binding sites for many transcription factors including AP1, ATF, E2F, HNF3b, NF1, NFκB, SP1, and SRF, and 2 poly(CA) stretches that may form Z-DNA structure. Transcriptional activation of CYR61 is exquisitely sensitive to a wide range of environmental perturbations, including stimulation by platelet-derived growth factor and basic fibroblast growth factor, transforming growth factor β1 (TGF-β1), growth hormone, the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), cAMP, vitamin D3, estrogen and tamoxifen, angiotensin II, hypoxia, UV light, and mechanical stretch.[3][7]

Protein structure and function

Structural domains

Full-length CYR61 protein contains 381 amino acids with an N-terminal secretory signal peptide followed by four structurally distinct domains.[13] The four CYR61 domains are, from N- to C-termini, the insulin-like growth factor binding protein (IGFBP) domain, von Willebrand type C repeats (vWC) domain, thrombospondin type 1 repeat domain (TSR), and the C-terminal (CT) domain that contains a cysteine-knot motif. CCN1 has unusually high cysteine residue content (10% or 38 in total). The number and spacing of cysteine residues are completely conserved among CYR61 (CCN1), CTGF (CCN2), NOV (CCN3), and WISP-1 (CCN4), and are largely conserved with WISP-2 (CCN5), which lacks precisely the CT domain, and WISP3 (CCN6), which lacks 4 cysteines in the vWC domain. CYR61 is glycosylated, although the regulation and function of glycosylation are unknown.

CCN1 Protein Structure

Integrin binding

CYR61 binds directly to various integrin receptors in a cell type-dependent manner, including integrin αvβ3 in endothelial cells,[14] α6β1 and heparan sulfate proteoglycans (HSPGs) in fibroblasts and smooth muscle cells[15][16] αIIbβ3 in activated platelets,[17] αMβ2 in monocytes and macrophages,[18][19] and αDβ2 in macrophage foam cells.[20] Where examined, syndecan-4 has been identified as the HSPG critical for CCN1 functions.[21][22] The CYR61 binding sites for some of these integrins have been mapped (Figure 1). Due to the cell type specificity of integrin expression, CYR61 acts through distinct integrins to mediate specific functions in different types of cells. For example, CYR61 induces angiogenic functions in endothelial cells through αvβ3,[23] and in fibroblasts promotes cellular senescence and enables TNFα to induce apoptosis through binding to α6β1-HSPGs.[22][24] However, CYR61 supports cell adhesion through all of the integrins identified above.

Cell signaling and function

As a cell adhesive substrate, CYR61 induces the activation of focal adhesion kinase, paxillin, RAC, and sustained activation of MAPK/ERK1-2.[25] In macrophages, CYR61 also activates the transcription factor NFκB and stimulates M1 polarization.[19] CYR61 activates Akt signaling in thymic epithelial cells, promoting their proliferation and thus thymic size growth.[26] CYR61 has potent angiogenic activity upon endothelial cells and induces neovascularization, first demonstrated in a corneal micropocket implant assay[27] and subsequently confirmed in a rabbit ischemic hindlimb model.[28] CYR61 also accelerates and promotes the chondrogenic differentiation of mouse limb bud mesenchymal cells,[29] and stimulates osteoblast differentiation but inhibits osteoclastogenesis.[30][31][32] Cyr61 is a strong inducer of reactive oxygen species accumulation in fibroblastic cells, and this activity underlies many CYR61-induced apoptosis and senescence.[22][24] CYR61 is able to support cell adhesion, stimulate cell migration, promote growth factor-induced cell proliferation and differentiation in some cell types, promote apoptosis in synergy with TNF family cytokines, and induce cellular senescence in fibroblasts.

Embryonic development

During embryo development in mice, Cyr61 is highly expressed in the cardiovascular, skeletal, and neuronal systems.[33][34] Cyr61 knockout mice are embryonic lethal due to defects in cardiac septal morphogenesis, deficient blood vessel formation in placenta, and compromised vascular integrity.[35][36] In Xenopus laevis, Cyr61 is required for normal gastrulation and modulation of Wnt signaling.[37]

Clinical relevance

CYR61 is highly expressed at sites of inflammation and wound repair, and is associated with diseases involving chronic inflammation and tissue injury.[3]

Wound healing and fibrosis

In skin wound healing, CYR61 is highly expressed in the granulation tissue by myofibroblasts, which proliferate and rapidly synthesize ECM to maintain tissue integrity and to promote regeneration of parenchymal cells.[38][39] However, excessive matrix deposition can lead to fibrosis, scarring, and loss of tissue function. In skin wounds, CYR61 accumulates in the granulation tissue as myofibroblasts proliferate, and eventually reaches a sufficiently high level to drive the myofibroblasts themselves into senescence, whereupon these cells cease to proliferate and express matrix-degrading enzymes.[24] Thus, CYR61 limits synthesis and deposition of ECM by myofibroblasts, reducing the risk of fibrosis during wound healing.[40] In addition to skin wound healing, CYR61 expression is elevated in remodeling cardiomyocytes after myocardial infarction,[41] in vascular injury,[16] and in the long bones during fracture repair.[42][43] Blockade of CYR61 by antibodies inhibits bone fracture healing in mice.[44] In the kidney, CYR61 is expressed in podocytes in normal adult and embryonic glomeruli, but expression is decreased in IgA nephropathy, diabetic nephropathy, and membranous nephropathy, particularly in diseased kidneys with severe mesangial expansion.[45] CYR61 induction of cellular senescence in the kidney is a potential therapy to limit fibrosis.[46]

Inflammation

CYR61 promotes the apoptotic functions of inflammatory cytokines such as TNFα, FasL, and TRAIL.[22][47][48] It also reprograms macrophages towards M1 polarization through αMβ2-mediated activation of NF-κB.[19] CYR61 is upregulated in patients with Crohn's disease and ulcerative colitis.[49] CYR61 supports the patrolling behavior of murine resident Ly6Clow monocytes along the endothelial in the steady state and is required for their accumulation under viral-mimicking vascular inflammation.[50]

Arthritis

CYR61 is highly expressed in collagen-induced arthritis in rodents, and inhibition of CCN1 expression correlates with suppression of inflammatory arthritis.[51] CYR61 is also found in articular cartilage from patients with osteoarthritis and appears to suppress ADAMTS4 (aggrecanase) activity, possibly leading to cartilage cell (chondrocyte) cloning.[52]

Vascular diseases

CYR61 is overexpressed in vascular smooth muscle cells of atherosclerotic lesions and in the neointima of restenosis after balloon angioplasty, both in rodent models and in humans.[16][18][53][54] Suppression of CYR61 expression results in reduced neointimal hyperplasia after balloon angioplasty, an effect that is reversed by delivery of CYR61 via gene transfer[55][56] In a mouse model of oxygen-induced retinopathy, expression of CYR61 in the vitreous humor produced significant beneficial effects in repairing damaged vasculature.[57]

Cancer

Angiogenesis is essential for the supply of oxygen and nutrients to nourish the growing tumor.[58] CYR61 is a powerful angiogenic inducer in vivo,[27][28] and it can also promote cancer cell proliferation, invasion, survival, epithelial–mesenchymal transition, and metastasis.[59][60][61][62] Accordingly, forced overexpression of CYR61 enhanced tumor growth in xenografts of breast cancer cells,[63] prostate cancer cells,[60] ovarian carcinoma cells,[64] and squamous carcinoma cells.[65] Clinically, CYR61 expression correlates with the tumor stage, tumor size, lymph node positivity, and poor prognosis in several cancers, including breast cancer,[63][66][67][68][69] prostate cancer,[70] glioma,[71] gastric adenocarcinoma,[72] and squamous cell carcinoma.[65]

However, CYR61 can also induce apoptosis and cellular senescence,[21][24][73] two well-established mechanisms of tumor suppression[74] Thus, whereas CYR61 can promote the proliferation of prostate cancer cells, it can also exacerbate apoptosis of these cells in the presence of the immune surveillance molecule TRAIL.[48][60][75] CYR61 has an inhibitory effect on some cancers, and suppresses tumor growth of non-small-cell lung cancer (NSCLC) cells,[76] endometrial adenocarcinoma cells,[77] and in melanoma cells.[78]

References

  1. ↑ "The human growth factor-inducible immediate early gene, CYR61, maps to chromosome 1p". Oncogene 14 (14): 1753–7. May 1997. doi:10.1038/sj.onc.1200986. PMID 9135077. 
  2. ↑ 2.0 2.1 Lau LF (October 2011). "CCN1/CYR61: the very model of a modern matricellular protein". Cell. Mol. Life Sci. 68 (19): 3149–63. doi:10.1007/s00018-011-0778-3. PMID 21805345. 
  3. ↑ 3.0 3.1 3.2 "Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets". Nature Reviews Drug Discovery 10 (12): 945–63. December 2011. doi:10.1038/nrd3599. PMID 22129992. 
  4. ↑ "Identification of a set of genes expressed during the G0/G1 transition of cultured mouse cells". EMBO J 4 (12): 3145–3151. 1985. doi:10.1002/j.1460-2075.1985.tb04057.x. PMID 3841511. 
  5. ↑ "All in the CCN family: essential matricellular signaling modulators emerge from the bunker". J. Cell Sci. 119 (Pt 23): 4803–4810. 2006. doi:10.1242/jcs.03270. PMID 17130294. 
  6. ↑ "The CCN family of proteins: structure-function relationships". Trends Biochem. Sci. 33 (10): 461–473. 2008. doi:10.1016/j.tibs.2008.07.006. PMID 18789696. 
  7. ↑ 7.0 7.1 "Functions and Mechanisms of Action of CCN Matricellular Proteins". Int. J. Biochem. Cell Biol. 41 (4): 771–783. 2009. doi:10.1016/j.biocel.2008.07.025. PMID 18775791. 
  8. ↑ "Proposal for a unified CCN nomenclature". Mol. Pathol. 56 (2): 127–128. 2003. doi:10.1136/mp.56.2.127. PMID 12665631. 
  9. ↑ "Matricellular proteins: extracellular modulators of cell function". Current Opinion in Cell Biology 14 (5): 608–616. 2002. doi:10.1016/S0955-0674(02)00361-7. PMID 12231357. 
  10. ↑ "The human growth factor-inducible immediate early gene, CYR61, maps to chromosome 1p". Oncogene 14 (14): 1753–1757. 1997. doi:10.1038/sj.onc.1200986. PMID 9135077. 
  11. ↑ "Promoter function and structure of the growth factor-inducible immediate early gene cyr61". Nucleic Acids Res. 19 (12): 3261–3267. 1991. doi:10.1093/nar/19.12.3261. PMID 2062642. 
  12. ↑ "MicroRNA-155 contributes to preeclampsia by down-regulating CYR61". Am. J. Obstet. Gynecol. 202 (5): 466–467. 2010. doi:10.1016/j.ajog.2010.01.057. PMID 20452491. 
  13. ↑ "Expression of cyr61, a growth factor-inducible immediate-early gene". Mol. Cell. Biol. 10 (7): 3569–3577. 1990. doi:10.1128/MCB.10.7.3569. PMID 2355916. 
  14. ↑ "Adhesion of human umbilical vein endothelial cells to the immediate-early gene product Cyr61 is mediated through integrin αvβ3". J. Biol. Chem. 273 (5): 3090–3096. 1998. doi:10.1074/jbc.273.5.3090. PMID 9446626. 
  15. ↑ "Adhesion of human skin fibroblasts to Cyr61 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans". J. Biol. Chem. 275 (32): 24953–24961. 2000. doi:10.1074/jbc.M003040200. PMID 10821835. 
  16. ↑ 16.0 16.1 16.2 "The angiogenic factor CYR61 supports vascular smooth muscle cell adhesion and stimulates chemotaxis through integrin α6β1 and cell surface heparan sulfate proteoglycans". Endocrinology 143 (4): 1441–1450. 2002. doi:10.1210/en.143.4.1441. PMID 11897702. 
  17. ↑ "Activation-dependent adhesion of human platelets to Cyr61 and Fisp12/Mouse connective tissue growth factor is mediated through integrin αIIbβ3". J. Biol. Chem. 274 (34): 24321–24327. 1999. doi:10.1074/jbc.274.34.24321. PMID 10446209. 
  18. ↑ 18.0 18.1 "Identification of integrin αMβ2 as an adhesion receptor on peripheral blood moncytes for Cyr61 (CCN1) and connective tissue growth factor (CCN2), immediate-early gene products expressed in atherosclerotic lesions". Blood 99 (12): 4457–4465. 2002. doi:10.1182/blood.V99.12.4457. PMID 12036876. 
  19. ↑ 19.0 19.1 19.2 "The matricellular protein CCN1 activates a pro-inflammatory genetic program in murine macrophages". J. Immunol. 184 (6): 3223–3232. 2010. doi:10.4049/jimmunol.0902792. PMID 20164416. 
  20. ↑ "Integrin αDβ2, an adhesion receptor up-regulated on macrophage foam cells, exhibits multiligand-binding properties". Blood 107 (4): 1643–1650. 2006. doi:10.1182/blood-2005-06-2509. PMID 16239428. 
  21. ↑ 21.0 21.1 "The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts". J. Cell Biol. 171 (3): 559–568. 2005. doi:10.1083/jcb.200504015. PMID 16275757. 
  22. ↑ 22.0 22.1 22.2 22.3 "Cytotoxicity of TNFα is regulated by Integrin-Mediated Matrix Signaling". EMBO J 26 (5): 1257–1267. 2007. doi:10.1038/sj.emboj.7601596. PMID 17318182. 
  23. ↑ "Proangiogenic activities of CYR61 (CCN1) mediated through integrins αvβ3 and α6β1 in human umbilical vein endothelial cells". J. Biol. Chem. 277 (48): 46248–46255. 2002. doi:10.1074/jbc.M209288200. PMID 12364323. 
  24. ↑ 24.0 24.1 24.2 24.3 "The Matricellular Protein CCN1/CYR61 Induces Fibroblast Senescence and Restricts Fibrosis in Cutaneous Wound Healing". Nat. Cell Biol. 12 (7): 676–685. 2010. doi:10.1038/ncb2070. PMID 20526329. 
  25. ↑ "The angiogenic factors Cyr61 and CTGF induce adhesive signaling in primary human skin fibroblasts". J. Biol. Chem. 276 (13): 10443–10452. 2001. doi:10.1074/jbc.M008087200. PMID 11120741. 
  26. ↑ Emre, Yalin; Irla, Magali; Dunand-Sauthier, Isabelle; Ballet, Romain; Meguenani, Mehdi; Jemelin, Stephane; Vesin, Christian; Reith, Walter et al. (2013-11-27). "Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output" (in en). Nature Communications 4: 2842. doi:10.1038/ncomms3842. PMID 24280864. Bibcode: 2013NatCo...4.2842E. 
  27. ↑ 27.0 27.1 "CYR61, product of a growth factor-inducible immediate-early gene, promotes angiogenesis and tumor growth". Proc. Natl. Acad. Sci. U.S.A. 95 (11): 6355–6360. 1998. doi:10.1073/pnas.95.11.6355. PMID 9600969. Bibcode: 1998PNAS...95.6355B. 
  28. ↑ 28.0 28.1 "Stimulation of angiogenesis by cyr61 gene: a new therapeutic candidate". Hum. Gene Ther. 13 (12): 1461–1470. 2002. doi:10.1089/10430340260185094. PMID 12215267. 
  29. ↑ "Cyr61, product of a growth factor-inducible immediate-early gene, regulates chondrogenesis in mouse limb bud mesenchymal cells". Dev. Biol. 192 (2): 492–508. 1997. doi:10.1006/dbio.1997.8766. PMID 9441684. 
  30. ↑ "CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3A-induced osteoblast differentiation of mesenchymal stem cells". Mol. Cell. Biol. 26 (8): 2955–2964. 2006. doi:10.1128/MCB.26.8.2955-2964.2006. PMID 16581771. 
  31. ↑ "The matricellular protein CYR61 inhibits osteoclastogenesis by a mechanism independent of αvβ3 and αvβ5". Endocrinology 148 (12): 5761–5768. 2007. doi:10.1210/en.2007-0473. PMID 17823253. 
  32. ↑ "CYR61 regulates BMP-2-dependent osteoblast differentiation through the αvβ3 integrin/integrin-linked kinase/ERK pathway". J. Biol. Chem. 285 (41): 31325–31336. 2010. doi:10.1074/jbc.M109.087122. PMID 20675382. 
  33. ↑ "Expression of the Growth Factor-Inducible Immediate Early Gene cyr61 Correlates with Chondrogenesis During Mouse Embryonic Development". Cell Growth & Differentiation 3 (9): 645–654. 1992. PMID 1419914. 
  34. ↑ "Promoter Function of the Angiogenic Inducer Cyr61 Gene in Transgenic Mice: Tissue Specificity, Inducibility During Wound Healing, and Role of the Serum Response Element". Endocrinology 142 (6): 2549–2557. 2001. doi:10.1210/endo.142.6.8208. PMID 11356704. 
  35. ↑ "CYR61 (CCN1) Is Essential for Placental Development and Vascular Integrity". Mol. Cell. Biol. 22 (24): 8709–8720. 2002. doi:10.1128/MCB.22.24.8709-8720.2002. PMID 12446788. 
  36. ↑ "The matricellular protein CCN1 is essential for cardiac development". Circ. Res. 99 (9): 961–969. 2006. doi:10.1161/01.RES.0000248426.35019.89. PMID 17023674. 
  37. ↑ "Xenopus Cyr61 regulates gastrulation movements and modulates Wnt signalling". Development 130 (11): 2429–2441. 2003. doi:10.1242/dev.00449. PMID 12702657. 
  38. ↑ "Wound repair and regeneration". Nature 453 (7193): 314–321. 2008. doi:10.1038/nature07039. PMID 18480812. Bibcode: 2008Natur.453..314G. 
  39. ↑ Wynn TA (2008). "Cellular and molecular mechanisms of fibrosis". The Journal of Pathology 214 (2): 199–210. doi:10.1002/path.2277. PMID 18161745. 
  40. ↑ "Cellular senescence controls fibrosis in wound healing". Aging 2 (9): 627–631. 2010. doi:10.18632/aging.100201. PMID 20930261. 
  41. ↑ "Regulation of proangiogenic factor CCN1 in cardiac muscle: impact of ischemia, pressure overload, and neurohumoral activation". Circulation 109 (18): 2227–2233. 2004. doi:10.1161/01.CIR.0000127952.90508.9D. PMID 15117851. 
  42. ↑ "Temporal expression of the chondrogenic and angiogenic growth factor CYR61 during fracture repair". J. Bone Miner. Res. 15 (6): 1014–1023. 2000. doi:10.1359/jbmr.2000.15.6.1014. PMID 10841170. 
  43. ↑ "Expression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24) during fracture healing". Bone 31 (4): 441–447. 2002. doi:10.1016/S8756-3282(02)00846-3. PMID 12398938. http://ousar.lib.okayama-u.ac.jp/5152. 
  44. ↑ "Vascular endothelial growth factor (VEGF)-induced up-regulation of CCN1 in osteoblasts mediates proangiogenic activities in endothelial cells and promotes fracture healing". J. Biol. Chem. 282 (37): 26746–26753. 2007. doi:10.1074/jbc.M705200200. PMID 17626014. 
  45. ↑ "Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney". Am. J. Physiol. Renal Physiol. 293 (4): F1363–72. October 2007. doi:10.1152/ajprenal.00205.2007. PMID 17699553. 
  46. ↑ "Cellular senescence in the aging and diseased kidney". Journal of Cell Communication and Signaling 12 (1): 69–82. 2018. doi:10.1007/s12079-017-0434-2. PMID 29260442. 
  47. ↑ "Fas-Mediated Apoptosis is Regulated by the Extracellular Matrix Protein CCN1 (CYR61) in vitro and in vivo". Mol. Cell. Biol. 29 (12): 3266–3279. 2009. doi:10.1128/MCB.00064-09. PMID 19364818. 
  48. ↑ 48.0 48.1 "The Matrix Protein CCN1 is Critical for Prostate Carcinoma Cell Proliferation and TRAIL-Induced Apoptosis". Mol. Cancer Res. 7 (7): 1045–1055. 2009. doi:10.1158/1541-7786.MCR-09-0017. PMID 19584265. 
  49. ↑ "Substance P-mediated expression of the pro-angiogenic factor CCN1 modulates the course of colitis". Am. J. Pathol. 173 (2): 400–410. 2008. doi:10.2353/ajpath.2008.080222. PMID 18599605. 
  50. ↑ Imhof, Beat A.; Jemelin, Stephane; Ballet, Romain; Vesin, Christian; Schapira, Marco; Karaca, Melis; Emre, Yalin (2016-08-01). "CCN1/CYR61-mediated meticulous patrolling by Ly6Clow monocytes fuels vascular inflammation" (in en). Proceedings of the National Academy of Sciences 113 (33): E4847–E4856. doi:10.1073/pnas.1607710113. ISSN 0027-8424. PMID 27482114. Bibcode: 2016PNAS..113E4847I. 
  51. ↑ "Simvastatin inhibits cytokine-stimulated Cyr61 expression in osteoblastic cells: a therapeutic benefit for arthritis". Arthritis Rheum. 63 (4): 1010–20. April 2011. doi:10.1002/art.27433. PMID 20191585. 
  52. ↑ "CCN1 (Cyr61) Is Overexpressed in Human Osteoarthritic Cartilage and Inhibits ADAMTS-4 (Aggrecanase 1) Activity". Arthritis & Rheumatology 67 (6): 1557–67. June 2015. doi:10.1002/art.39078. PMID 25709087. 
  53. ↑ "Expression of CYR61, an angiogenic immediate early gene, in arteriosclerosis and its regulation by angiotensin II". Circulation 106 (2): 254–260. 2002. doi:10.1161/01.CIR.0000021426.87274.62. PMID 12105167. 
  54. ↑ "Heregulin, cysteine rich-61 and matrix metalloproteinase 9 expression in human carotid atherosclerotic plaques: relationship with clinical data". Eur. J. Vasc. Endovasc. Surg. 32 (3): 238–245. 2006. doi:10.1016/j.ejvs.2006.01.026. PMID 16774841. 
  55. ↑ "Forkhead transcription factor FOXO3a is a negative regulator of angiogenic immediate early gene CYR61, leading to inhibition of vascular smooth muscle cell proliferation and neointimal hyperplasia". Circ. Res. 100 (3): 372–380. 2007. doi:10.1161/01.RES.0000257945.97958.77. PMID 17234971. 
  56. ↑ "CCN1 Knockdown Suppresses Neointimal Hyperplasia in a Rat Artery Balloon Injury Model". Arterioscler. Thromb. Vasc. Biol. 28 (6): 1077–1083. 2008. doi:10.1161/ATVBAHA.108.162362. PMID 18388330. 
  57. ↑ "The matricellular protein cysteine-rich protein 61 (CCN1/Cyr61) enhances physiological adaptation of retinal vessels and reduces pathological neovascularization associated with ischemic retinopathy". J. Biol. Chem. 286 (11): 9542–54. March 2011. doi:10.1074/jbc.M110.198689. PMID 21212276. 
  58. ↑ Folkman J (2006). "Angiogenesis". Annu. Rev. Med. 57: 1–18. doi:10.1146/annurev.med.57.121304.131306. PMID 16409133. 
  59. ↑ "CYR61 and αVβ5 Integrin Cooperate to Promote Invasion and Metastasis of Tumors Growing in Preirradiated Stroma". Cancer Res 68 (18): 7323–7331. 2008. doi:10.1158/0008-5472.CAN-08-0841. PMID 18794119. 
  60. ↑ 60.0 60.1 60.2 "Involvement of Cyr61 in growth, migration, and metastasis of prostate cancer cells". Br. J. Cancer 99 (10): 1656–1667. 2008. doi:10.1038/sj.bjc.6604712. PMID 18941464. 
  61. ↑ "Genomic and phenotypic analysis reveals a key role for CCN1 (CYR61) in BAG3-modulated adhesion and invasion". J. Pathol. 218 (4): 495–504. 2009. doi:10.1002/path.2557. PMID 19402132. PMC 7316387. https://zenodo.org/record/1229300. 
  62. ↑ "Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis". Mol. Cancer 10: 8. 2011. doi:10.1186/1476-4598-10-8. PMID 21232118. 
  63. ↑ 63.0 63.1 "Breast cancer. Cyr61 is overexpressed, estrogen-inducible, and associated with more advanced disease". J. Biol. Chem. 276 (17): 14187–14194. 2001. doi:10.1074/jbc.M009755200. PMID 11297518. 
  64. ↑ "Ovarian carcinomas: CCN genes are aberrantly expressed and CCN1 promotes proliferation of these cells". Clin. Cancer Res. 11 (20): 7243–7254. 2005. doi:10.1158/1078-0432.CCR-05-0231. PMID 16243794. 
  65. ↑ 65.0 65.1 "Expression of Cyr61 (CCN1) in human oral squamous cell carcinoma: An independent marker for poor prognosis". Head Neck 32 (12): 1665–1673. 2010. doi:10.1002/hed.21381. PMID 20848406. 
  66. ↑ "Expression and function of CYR61, an angiogenic factor, in breast cancer cell lines and tumor biopsies". Cancer Res 60 (20): 5603–5607. 2000. PMID 11059746. 
  67. ↑ "Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features". Cancer Res 61 (24): 8917–8923. 2001. PMID 11751417. 
  68. ↑ "Differential expression of the CCN family members Cyr61, CTGF and Nov in human breast cancer". Endocr. Relat. Cancer 11 (4): 781–791. 2004. doi:10.1677/erc.1.00825. PMID 15613452. 
  69. ↑ "Functional domains of CCN1 (Cyr61) regulate breast cancer progression". Int. J. Oncol. 33 (1): 59–67. 2008. doi:10.3892/ijo.33.1.59. PMID 18575751. 
  70. ↑ "Extracellular matrix associated protein CYR61 is linked to prostate cancer development". J. Urol. 183 (4): 1604–1610. 2010. doi:10.1016/j.juro.2009.12.006. PMID 20172544. 
  71. ↑ "Cyr61 mediates hepatocyte growth factor-dependent tumor cell growth, migration, and Akt activation". Cancer Res 70 (7): 2932–2941. 2010. doi:10.1158/0008-5472.CAN-09-3570. PMID 20233866. 
  72. ↑ "Cyr61 induces gastric cancer cell motility/invasion via activation of the integrin/nuclear factor-κB/cyclooxygenase-2 signaling pathway". Clin. Cancer Res. 11 (16): 5809–5820. 2005. doi:10.1158/1078-0432.CCR-04-2639. PMID 16115920. 
  73. ↑ "Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines". J. Cell Commun. Signal 4 (1): 63–69. 2010. doi:10.1007/s12079-009-0080-4. PMID 19898959. 
  74. ↑ Schmitt CA (2003). "Senescence, apoptosis and therapy--cutting the lifelines of cancer". Nature Reviews Cancer 3 (4): 286–295. doi:10.1038/nrc1044. PMID 12671667. 
  75. ↑ "Induction and function of CYR61 (CCN1) in prostatic stromal and epithelial cells: CYR61 is required for prostatic cell proliferation". Prostate 61 (4): 305–317. 2004. doi:10.1002/pros.20098. PMID 15389821. 
  76. ↑ "Cyr61, a member of CCN family, is a tumor suppressor in non-small cell lung cancer". J. Biol. Chem. 276 (50): 47709–47714. 2001. doi:10.1074/jbc.M107878200. PMID 11598125. 
  77. ↑ "Cyr61 suppresses growth of human endometrial cancer cells". J. Biol. Chem. 279 (51): 53087–53096. 2004. doi:10.1074/jbc.M410254200. PMID 15471875. 
  78. ↑ "Silencing cAMP-response element binding protein (CREB) identifies cysteine-rich protein 61 (CYR61) as a tumor suppressor gene in melanoma". J. Biol. Chem. 284 (38): 26194–26206. 2009. doi:10.1074/jbc.M109.019836. PMID 19632997. 



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