Biology:CYR61

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

CCN1 is a secreted, extracellular matrix (ECM)-associated signaling protein of the CCN family (CCN intercellular signaling protein).[2][3] CCN1 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, CCN1 is critical for cardiac septal morphogenesis, blood vessel formation in placenta, and vascular integrity. In adulthood CCN1 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

CCN1 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

CCN1 is located at human chromosome 1p22.3, whereas the mouse CCN1 gene is located at chromosome 3, 72.9cM.[10] The mouse CCN1 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 CCN1 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 CCN1 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 CCN1 protein contains 381 amino acids with an N-terminal secretory signal peptide followed by four structurally distinct domains.[13] The four CCN1 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 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. CCN1 is glycosylated, although the regulation and function of glycosylation are unknown.

CCN1 Protein Structure

Integrin binding

CCN1 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 CCN1 binding sites for some of these integrins have been mapped (Figure 1). Due to the cell type specificity of integrin expression, CCN1 acts through distinct integrins to mediate specific functions in different types of cells. For example, CCN1 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, CCN1 supports cell adhesion through all of the integrins identified above.

Cell signaling and function

As a cell adhesive substrate, CCN1 induces the activation of focal adhesion kinase, paxillin, RAC, and sustained activation of MAPK/ERK1-2.[25] In macrophages, CCN1 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] CCN1 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] CCN1 also accelerates and promotes the chondrogenic differentiation of mouse limb bud mesenchymal cells,[29] and stimulates osteoblast differentiation but inhibits osteoclastogenesis.[30][31][32] CCN1 is a strong inducer of reactive oxygen species accumulation in fibroblastic cells, and this activity underlies many CCN1-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, CCN1 is highly expressed in the cardiovascular, skeletal, and neuronal systems.[33][34] CCN1 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, CCN1 is required for normal gastrulation and modulation of Wnt signaling.[37]

Clinical relevance

CCN1 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, CCN1 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, CCN1 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, CCN1 limits synthesis and deposition of ECM by myofibroblasts, reducing the risk of fibrosis during wound healing.[40] In addition to skin wound healing, CCN1 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 CCN1 by antibodies inhibits bone fracture healing in mice.[44] In the kidney, CCN1 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

CCN1 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] CCN1 is upregulated in patients with Crohn's disease and ulcerative colitis.[49] CCN1 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

CCN1 is highly expressed in collagen-induced arthritis in rodents, and inhibition of CCN1 expression correlates with suppression of inflammatory arthritis.[51] CCN1 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

CCN1 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 CCN1 expression results in reduced neointimal hyperplasia after balloon angioplasty, an effect that is reversed by delivery of CCN1 via gene transfer[55][56] In a mouse model of oxygen-induced retinopathy, expression of CCN1 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] CCN1 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 CCN1 enhanced tumor growth in xenografts of breast cancer cells,[63] prostate cancer cells,[60] ovarian carcinoma cells,[64] and squamous carcinoma cells.[65] Clinically, CCN1 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, CCN1 can also induce apoptosis and cellular senescence,[21][24][73] two well-established mechanisms of tumor suppression[74] Thus, whereas CCN1 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] CCN1 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, CCN1, maps to chromosome 1p". Oncogene 14 (14): 1753–1757. May 1997. doi:10.1038/sj.onc.1200986. PMID 9135077. 
  2. ↑ 2.0 2.1 "CCN1/CYR61: the very model of a modern matricellular protein". Cellular and Molecular Life Sciences 68 (19): 3149–3163. October 2011. 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): 945–963. 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". The EMBO Journal 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". Journal of Cell Science 119 (Pt 23): 4803–4810. 2006. doi:10.1242/jcs.03270. PMID 17130294. 
  6. ↑ "The CCN family of proteins: structure-function relationships". Trends in Biochemical Sciences 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". The International Journal of Biochemistry & Cell Biology 41 (4): 771–783. 2009. doi:10.1016/j.biocel.2008.07.025. PMID 18775791. 
  8. ↑ "Proposal for a unified CCN nomenclature". Molecular Pathology 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, CCN1, 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 ccn1". Nucleic Acids Research 19 (12): 3261–3267. 1991. doi:10.1093/nar/19.12.3261. PMID 2062642. 
  12. ↑ "MicroRNA-155 contributes to preeclampsia by down-regulating CCN1". American Journal of Obstetrics and Gynecology 202 (5): 466–467. 2010. doi:10.1016/j.ajog.2010.01.057. PMID 20452491. 
  13. ↑ "Expression of ccn1, a growth factor-inducible immediate-early gene". Molecular and Cellular Biology 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 CCN1 is mediated through integrin αvβ3". The Journal of Biological Chemistry 273 (5): 3090–3096. 1998. doi:10.1074/jbc.273.5.3090. PMID 9446626. 
  15. ↑ "Adhesion of human skin fibroblasts to CCN1 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans". The Journal of Biological Chemistry 275 (32): 24953–24961. 2000. doi:10.1074/jbc.M003040200. PMID 10821835. 
  16. ↑ 16.0 16.1 16.2 "The angiogenic factor CCN1 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 CCN1 and Fisp12/Mouse connective tissue growth factor is mediated through integrin αIIbβ3". The Journal of Biological Chemistry 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 CCN1 (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". Journal of Immunology 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". The Journal of Cell Biology 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". The EMBO Journal 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". The Journal of Biological Chemistry 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". Nature Cell Biology 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". The Journal of Biological Chemistry 276 (13): 10443–10452. 2001. doi:10.1074/jbc.M008087200. PMID 11120741. 
  26. ↑ "Thymic epithelial cell expansion through matricellular protein CYR61 boosts progenitor homing and T-cell output". Nature Communications 4 (1): 2842. 2013-11-27. 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". Proceedings of the National Academy of Sciences of the United States of America 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". Human Gene Therapy 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". Developmental Biology 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". Molecular and Cellular Biology 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". The Journal of Biological Chemistry 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". Molecular and Cellular Biology 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". Circulation Research 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. ↑ "Cellular and molecular mechanisms of fibrosis". The Journal of Pathology 214 (2): 199–210. January 2008. 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". Journal of Bone and Mineral Research 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". The Journal of Biological Chemistry 282 (37): 26746–26753. 2007. doi:10.1074/jbc.M705200200. PMID 17626014. 
  45. ↑ "Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney". American Journal of Physiology. Renal Physiology 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". Molecular and Cellular Biology 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". Molecular Cancer Research 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". The American Journal of Pathology 173 (2): 400–410. 2008. doi:10.2353/ajpath.2008.080222. PMID 18599605. 
  50. ↑ "CCN1/CYR61-mediated meticulous patrolling by Ly6Clow monocytes fuels vascular inflammation". Proceedings of the National Academy of Sciences of the United States of America 113 (33): E4847–56. August 2016. doi:10.1073/pnas.1607710113. PMID 27482114. Bibcode: 2016PNAS..113E4847I. 
  51. ↑ "Simvastatin inhibits cytokine-stimulated Cyr61 expression in osteoblastic cells: a therapeutic benefit for arthritis". Arthritis and Rheumatism 63 (4): 1010–1020. 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): 1557–1567. 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". European Journal of Vascular and Endovascular Surgery 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". Circulation Research 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". Arteriosclerosis, Thrombosis, and Vascular Biology 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". The Journal of Biological Chemistry 286 (11): 9542–9554. March 2011. doi:10.1074/jbc.M110.198689. PMID 21212276. 
  58. ↑ "Angiogenesis". Annual Review of Medicine 57 (1): 1–18. 2006-02-01. 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 Research 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". British Journal of 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". The Journal of Pathology 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". Molecular 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". The Journal of Biological Chemistry 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". Clinical Cancer Research 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 Research 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 Research 61 (24): 8917–8923. 2001. PMID 11751417. 
  68. ↑ "Differential expression of the CCN family members Cyr61, CTGF and Nov in human breast cancer". Endocrine-Related Cancer 11 (4): 781–791. 2004. doi:10.1677/erc.1.00825. PMID 15613452. 
  69. ↑ "Functional domains of CCN1 (Cyr61) regulate breast cancer progression". International Journal of Oncology 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". The Journal of Urology 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 Research 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". Clinical Cancer Research 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". Journal of Cell Communication and Signaling 4 (1): 63–69. 2010. doi:10.1007/s12079-009-0080-4. PMID 19898959. 
  74. ↑ "Senescence, apoptosis and therapy--cutting the lifelines of cancer". Nature Reviews. Cancer 3 (4): 286–295. April 2003. 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". The 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". The Journal of Biological Chemistry 276 (50): 47709–47714. 2001. doi:10.1074/jbc.M107878200. PMID 11598125. 
  77. ↑ "Cyr61 suppresses growth of human endometrial cancer cells". The Journal of Biological Chemistry 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". The Journal of Biological Chemistry 284 (38): 26194–26206. 2009. doi:10.1074/jbc.M109.019836. PMID 19632997. 




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