CCN1/CYR61: The very model of a modern matricellular protein

Cellular and Molecular Life Sciences

Volumn 68, Issue 19, 2011, Pages 3149-3163

  Lau, Lester F ^a  

^a UNIVERSITY OF ILLINOIS   (United States)

Author keywords

Angiogenesis; Apoptosis; Fibrosis; Integrins; Reactive oxygen species; Senescence; Signal transduction; Tumorigenesis; Wound healing

Indexed keywords

CELL ADHESION MOLECULE; CYSTEINE RICH PROTEIN 61; MATRIX PROTEIN; PROTEOHEPARAN SULFATE; REACTIVE OXYGEN METABOLITE; TUMOR NECROSIS FACTOR ALPHA; VASCULOTROPIN; VITRONECTIN RECEPTOR;

ANGIOGENESIS; APOPTOSIS; BIOACCUMULATION; BONE DEVELOPMENT; CARCINOGENESIS; CCN1 GENE; CELL ADHESION; CELL AGING; CELL FUNCTION; CELL MIGRATION; CELL NUCLEUS; CELL PROLIFERATION; CELL SURFACE; CELL SURVIVAL; CELL TYPE; CHONDROGENESIS; CHRONIC INFLAMMATION; DEVELOPMENTAL DISORDER; DNA SYNTHESIS; EMBRYO DEVELOPMENT; EXTRACELLULAR MATRIX; FIBRIN FORMATION; FIBROSIS; GENE; HUMAN; INFLAMMATION; KIDNEY DISEASE; MALIGNANT NEOPLASTIC DISEASE; MALIGNANT TRANSFORMATION; MOLECULAR MODEL; NONHUMAN; PATHOPHYSIOLOGY; PREGNANCY; PROTEIN BINDING; PROTEIN CARBOHYDRATE INTERACTION; PROTEIN DOMAIN; PROTEIN EXPRESSION; PROTEIN FAMILY; PROTEIN FUNCTION; PROTEIN MODIFICATION; PROTEIN PROCESSING; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; SKIN INJURY; TRANSCRIPTION REGULATION; VASCULAR DISEASE; WOUND HEALING;

ANIMALS; CELL ADHESION; CELL AGING; CELL MOVEMENT; CELL PROLIFERATION; CYSTEINE-RICH PROTEIN 61; DNA; EMBRYONIC DEVELOPMENT; FEMALE; GENE EXPRESSION REGULATION; INTEGRINS; MICE; MODELS, BIOLOGICAL; NEOPLASMS; PREGNANCY; REACTIVE OXYGEN SPECIES; RECEPTORS, CELL SURFACE; SIGNAL TRANSDUCTION; WOUND HEALING;

EID: 80052925829     PISSN: 1420682X     EISSN: 14209071     Source Type: Journal    
DOI: 10.1007/s00018-011-0778-3     Document Type: Review

References (163)

1. Bornstein P (1995) Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J Cell Biol 130:503-506
2. Jun J-I, Lau LF (2010) The matricellular protein CCN1/CYR61 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nat Cell Biol 12:676-685
3. Kyriakides TR, Bornstein P (2003) Matricellular proteins as modulators of wound healing and the foreign body response. Thromb Haemost 90:986-992 (Pubitemid 38008022)
4. Chiodoni C, Colombo MP, Sangaletti S (2010) Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis. Cancer Metastasis Rev 29:295-307
5. Lau LF, Nathans D (1985) Identification of a set of genes expressed during the G0/G1 transition of cultured mouse cells. EMBO J 4:3145-3151
6. Lau LF, Nathans D (1987) Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. Proc Natl Acad Sci USA 84:1182-1186 (Pubitemid 17027316)
7. Simmons DL, Levy DB, Yannoni Y, Erikson RL (1989) Identification of a phorbol ester-repressible v-src-inducible gene. Proc Natl Acad Sci USA 86:1178-1182 (Pubitemid 19061517)
8. O'Brien TP, Yang GP, Sanders L, Lau LF (1990) Expression of cyr61, a growth factor-inducible immediate-early gene. Mol Cell Biol 10:3569-3577 (Pubitemid 20198182)
9. Brigstock DR (1999) The connective tissue growth factor/cysteine- rich 61/nephroblastoma overexpressed (CCN) family. Endocr Rev 20:189-206 (Pubitemid 29339590)
10. Lau LF, Lam SC (1999) The CCN family of angiogenic regulators: the integrin connection. Exp Cell Res 248:44-57 (Pubitemid 29393928)
11. Fernando CA, Conrad PA, Bartels CF, Marques T, To M, Balow SA, Nakamura Y, Warman ML (2010) Temporal and spatial expression of CCN genes in zebrafish. Dev Dyn 239:1755-1767
12. Brigstock DR, Goldschmeding R, Katsube KI, Lam SC, Lau LF, Lyons K, Naus C, Perbal B, Riser B, Takigawa M et al (2003) Proposal for a unifiedCCNnomenclature. Mol Pathol 56:127-128
13. Yang GP, Lau LF (1991) Cyr61, product of a growth factorinducible immediate early gene, is associated with the extracellular matrix and the cell surface. Cell Growth Differ 2:351-357
14. Kireeva ML, Mo F-E, Yang GP, Lau LF (1996) Cyr61, product of a growth factor-inducible immediate-early gene, promotes cell proliferation, migration, and adhesion. Mol Cell Biol 16:1326-1334 (Pubitemid 26095602)
15. Kireeva ML, Lam SCT, Lau LF (1998) Adhesion of human umbilical vein endothelial cells to the immediate-early gene product Cyr61 is mediated through integrin αvβ3. J Biol Chem 273:3090-3096 (Pubitemid 28133964)
16. Leask A, Abraham DJ (2006) All in the CCN family: essential matricellular signaling modulators emerge from the bunker. J Cell Sci 119:4803-4810 (Pubitemid 46017793)
17. Holbourn KP, Acharya KR, Perbal B (2008) The CCN family of proteins: structure-function relationships. Trends Biochem Sci 33:461-473
18. Chen C-C, Lau LF (2009) Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol 41:771-783
19. Brunner A, Chinn J, Neubauer M, Purchio AF (1991) Identification of a gene family regulated by transforming growth factorβ. DNA Cell Biol 10:293-300
20. Cui TX, Lin G, Lapensee CR, Calinescu AA, Rathore M, Streeter C, Piwien-Pilipuk G, Lanning N, Jin H, Carter-Su C et al. (2011) C/EBPβ mediates growth hormone-regulated expression of multiple target genes. Mol Endocrinol 25:681-693
21. Schutze N, Lechner A, Groll C, Siggelkow H, Hufner M, Kohrle J, Jakob F (1998) The human analog of murine cysteine-rich protein 61 is a 1α, 25-dihydroxyvitamin D3 responsive immediate early gene in human fetal osteoblasts: regulation by cytokines, growth factors, and serum. Endocrinology 139:1761-1770 (Pubitemid 28513835)
22. Rivera-Gonzalez R, Petersen DN, Tkalcevic G, Thompson DD, Brown TA (1998) Estrogen-induced genes in the uterus of ovariectomized rats and their regulation by droloxifene and tamoxifen. J Steroid Biochem Molec Biol 64:13-24 (Pubitemid 28132843)
23. Hilfiker A, Hilfiker-Kleiner D, Fuchs M, Kaminski K, Lichtenberg A, Rothkotter HJ, Schieffer B, Drexler H (2002) Expression of CYR61, an angiogenic immediate early gene, in arteriosclerosis and its regulation by angiotensin II. Circulation 106:254-260 (Pubitemid 34761308)
24. Hilfiker-Kleiner D, Kaminski K, Kaminska A, Fuchs M, Klein G, Podewski E, Grote K, Kiian I, Wollert KC, Hilfiker A et al (2004) Regulation of proangiogenic factor CCN1 in cardiac muscle: impact of ischemia, pressure overload, and neurohumoral activation. Circulation 109:2227-2233 (Pubitemid 38625401)
25. Kunz M, Moeller S, Koczan D, Lorenz P, Wenger RH, Glocker MO, Thiesen HJ, Gross G, Ibrahim SM (2003) Mechanisms of hypoxic gene regulation of angiogenesis factor Cyr61 in melanoma cells. J Biol Chem 278:45651-45660 (Pubitemid 37432707)
26. Quan T, He T, Shao Y, Lin L, Kang S, Voorhees JJ, Fisher GJ (2006) Elevated cysteine-rich 61 mediates aberrant collagen homeostasis in chronologically aged and photoaged human skin. Am J Pathol 169:482-490 (Pubitemid 44156309)
27. Chaqour B, Goppelt-Struebe M (2006) Mechanical regulation of the Cyr61/CCN1 and CTGF/CCN2 proteins. FEBS J 273:3639-3649
28. Kivela R, Kyrolainen H, Selanne H, Komi PV, Kainulainen H, Vihko V (2007) A single bout of exercise with high mechanical loading induces the expression of Cyr61/CCN1 and CTGF/ CCN2 in human skeletal muscle. J Appl Physiol 103:1395-1401 (Pubitemid 47605979)
29. Kim SM, Park JH, Chung SK, Kim JY, Hwang HY, Chung KC, Jo I, Park SI, Nam JH (2004) Coxsackievirus B3 infection induces cyr61 activation via JNK to mediate cell death. J Virol 78:13479-13488 (Pubitemid 39612748)
30. Wiedmaier N, Muller S, Koberle M, Manncke B, Krejci J, Autenrieth IB, Bohn E (2008) Bacteria induce CTGF and CYR61 expression in epithelial cells in a lysophosphatidic acid receptor-dependent manner. Int J Med Microbiol 298:231-243 (Pubitemid 351318367)
31. Kular L, Pakradouni J, Kitabgi P, Laurent M, Martinerie C (2010) The CCN family: a new class of inflammation modulators? Biochimie 93:377-388
32. Kurozumi K, Hardcastle J, Thakur R, Shroll J, Nowicki M, Otsuki A, Chiocca EA, Kaur B (2008) Oncolytic HSV-1 infection of tumors induces angiogenesis and upregulates CYR61. Mol Ther 16:1382-1391
33. Gashaw I, Stiller S, Boing C, Kimmig R, Winterhager E (2008) Premenstrual regulation of the pro-angiogenic factor CYR61 in human endometrium. Endocrinology 149:2261-2269 (Pubitemid 351574533)
34. Pendurthi UR, Allen KE, Ezban M, Rao LV (2000) Factor VIIa and thrombin induce the expression of Cyr61 and connective tissue growth factor, extracellular matrix signaling proteins that could act as possible downstream mediators in factor VIIa x tissue factor-induced signal transduction. J Biol Chem 275:14632-14641 (Pubitemid 30339754)
35. Walsh CT, Radeff-Huang J, Matteo R, Hsiao A, Subramaniam S, Stupack D, Brown JH (2008) Thrombin receptor and RhoA mediate cell proliferation through integrins and cysteine-rich protein 61. FASEB J 22:4011-4021
36. Liang Y, Li C, Guzman VM, Evinger AJ III, Protzman CE, Krauss AH, Woodward DF (2003) Comparison of PGF2a, Bimatoprost (prostamide) and butaprost (EP2 agonist) on Cyr61 and CTGF gene expression. J Biol Chem 278:27267-27277
37. Kim YM, Lim SC, Han CY, Kay HY, Cho IJ, Ki SH, Lee MY, Kwon HM, Lee CH, Kim SG (2011) Ga12/13 induction of CYR61 in association with arteriosclerotic intimal hyperplasia: effect of sphingosine-1-phosphate. Arterioscler Thromb Vasc Biol 31:861-869
38. Walsh CT, Stupack D, Brown JH (2008) G protein-coupled receptors go extracellular: RhoA integrates the integrins. Mol Interv 8:165-173
39. Latinkic BV, O'Brien TP, Lau LF (1991) Promoter function and structure of the growth factor-inducible immediate early gene cyr61. Nucleic Acids Res 19:3261-3267 (Pubitemid 21912679)
40. Latinkic BV, Mo F-E, Greenspan JA, Copeland NG, Gilbert DJ, Jenkins NA, Lau LF (2001) 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 142:2549-2557 (Pubitemid 32473111)
41. Hanna M, Liu H, Amir J, Sun Y, Morris SW, Siddiqui MA, Lau LF, Chaqour B (2009) Mechanical regulation of the proangiogenic factor CCN1/CYR61 gene requires the combined activities of MRTF-A and CREB-binding protein histone acetyltransferase. J Biol Chem 284:23125-23136
42. Grote K, Bavendiek U, Grothusen C, Flach I, Hilfiker-Kleiner D, Drexler H, Schieffer B (2004) Stretch-inducible expression of the angiogenic factor CCN1 in vascular smooth muscle cells is mediated by Egr-1. J Biol Chem 279:55675-55681 (Pubitemid 40066572)
43. Meyuhas R, Pikarsky E, Tavor E, Klar A, Abramovitch R, Hochman J, Lago TG, Honigman A (2008) A key role for cyclic AMP-responsive element binding protein in hypoxia-mediated activation of the angiogenesis factor CCN1 (CYR61) in tumor cells. Mol Cancer Res 6:1397-1409
44. Wolf N, Yang W, Dunk CE, Gashaw I, Lye SJ, Ring T, Schmidt M, Winterhager E, Gellhaus A (2010) Regulation of the matricellular proteins CYR61 (CCN1) and NOV (CCN3) by hypoxiainducible factor-1a and transforming-growth factor-b3 in the human trophoblast. Endocrinology 151:2835-2845
45. Chan SW, Lim CJ, Chong YF, Venkatesan PA, Huang C, Hong W (2011) Hippo pathway-independent restriction of TAZ and YAP by angiomotin. J Biol Chem 286:7018-7026
46. Zhang H, Pasolli HA, Fuchs E (2011) Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. Proc Natl Acad Sci USA 108:2270-2275
47. Leng E, Malcolm T, Tai G, Estable M, Sadowski I (2002) Organization and expression of the cyr61 gene in normal human fibroblasts. J Biomed Sci 9:59-67 (Pubitemid 34124208)
48. Hirschfeld M, zur HA, Bettendorf H, Jager M, Stickeler E (2009) Alternative splicing of Cyr61 is regulated by hypoxia and significantly changed in breast cancer. Cancer Res 69:2082-2090
49. Zhang Y, Diao Z, Su L, Sun H, Li R, Cui H, Hu Y (2010) MicroRNA-155 contributes to preeclampsia by down-regulating CYR61. Am J Obstet Gynecol 202:466-467
50. Johannes G, Carter MS, Eisen MB, Brown PO, Sarnow P (1999) Identification of eukaryotic mRNAs that are translated at reduced cap binding complex eIF4F concentrations using a cDNA microarray. Proc Natl Acad Sci USA 96:13118-13123
51. Mukudai Y, Kubota S, Eguchi T, Sumiyoshi K, Janune D, Kondo S, Shintani S, Takigawa M (2010) A coding RNA segment that enhances the ribosomal recruitment of chicken ccn1 mRNA. J Cell Biochem 111:1607-1618
52. Pendurthi UR, Tran TT, Post M, Rao LV (2005) Proteolysis of CCN1 by plasmin: functional implications. Cancer Res 65:9705-9711 (Pubitemid 41541446)
53. Lau LF, Lam SCT (2005) Integrin-mediated CCN functions. In: Perbal B, Takigawa M (eds) CCN proteins: a new family of cell growth and differentiation regulators. Imperial College Press, London, pp 61-79
54. Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673-687 (Pubitemid 35283958)
55. Chen N, Chen CC, Lau LF (2000) Adhesion of human skin fibroblasts to Cyr61 is mediated through integrin α6β1 and cell surface heparan sulfate proteoglycans. J Biol Chem 275:24953-24961 (Pubitemid 30626603)
56. Grzeszkiewicz TM, Lindner V, Chen N, Lam SCT, Lau LF (2002) The angiogenic factor CYR61 supports vascular smooth muscle cell adhesion and stimulates chemotaxis through integrin α6β1 and cell surface heparan sulfate proteoglycans. Endocrinology 143:1441-1450 (Pubitemid 34274374)
57. Jedsadayanmata A, Chen CC, Kireeva ML, Lau LF, Lam SC (1999) Activation-dependent adhesion of human platelets to Cyr61 and Fisp12/Mouse connective tissue growth factor is mediated through integrin αIIbβ3. J Biol Chem 274:24321-24327
58. Schober JM, Chen N, Grzeszkiewicz TM, Emeson EE, Ugarova TP, Ye RD, Lau LF, Lam SCT (2002) 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 99:4457-4465 (Pubitemid 34627215)
59. Bai T, Chen C-C, Lau LF (2010) The matricellular protein CCN1 activates a pro-inflammatory genetic program in murine macrophages. J Immunol 184:3223-3232
60. Yakubenko VP, Yadav SP, Ugarova TP (2006) Integrin αDβ2, an adhesion receptor up-regulated on macrophage foam cells, exhibits multiligand-binding properties. Blood 107:1643-1650 (Pubitemid 43242404)
61. Todorovic V, Chen C-C, Hay N, Lau LF (2005) The matrix protein CCN1 (CYR61) induces apoptosis in fibroblasts. J Cell Biol 171:559-568 (Pubitemid 41586944)
62. Chen C-C, Young JL, Monzon RI, Chen N, Todorovic V, Lau LF (2007) Cytotoxicity of TNFα is regulated by integrin-mediated matrix signaling. EMBO J 26:1257-1267 (Pubitemid 46398716)
63. Schober JM, Lau LF, Ugarova TP, Lam SC (2003) Identification of a novel integrin αMβ2 binding site in CCN1 (CYR61), a matricellular protein expressed in healing wounds and atherosclerotic lesions. J Biol Chem 278:25808-25815 (Pubitemid 36835339)
64. Leu S-J, Liu Y, Chen N, Chen CC, Lam SC, Lau LF (2003) Identification of a novel integrin α6β1 binding site in the angiogenic Inducer CCN1 (CYR61). J Biol Chem 278:33801-33808 (Pubitemid 37553214)
65. Chen N, Leu S-J, Todorovic V, Lam SCT, Lau LF (2004) Identification of a novel integrin αvβ3 binding site in CCN1 (CYR61) critical for pro-angiogenic activities in vascular endothelial cells. J Biol Chem 279:44166-44176 (Pubitemid 39390724)
66. Leu S-J, Chen N, Chen C-C, Todorovic V, Bai T, Juric V, Liu Y, Yan G, Lam SCT, Lau LF (2004) Targeted mutagenesis of the matricellular protein CCN1 (CYR61): selective inactivation of integrin α6β1-heparan sulfate proteoglycan coreceptor-mediated cellular activities. J Biol Chem 279:44177-44187 (Pubitemid 39390725)
67. Segarini PR, Nesbitt JE, Li D, Hayes LG, Yates JR III, Carmichael DF (2001) The low density lipoprotein receptor-related protein/α2- Macroglobulin receptor is a receptor for connective tissue growth factor (CTGF). J Biol Chem 276:40659-40667
68. Wahab NA, Weston BS, Mason RM (2005) Connective tissue growth factor CCN2 interacts with and activates the tyrosine kinase receptor TrkA. J Am Soc Nephrol 16:340-351 (Pubitemid 41725129)
69. Sakamoto K, Yamaguchi S, Ando R, Miyawaki A, Kabasawa Y, Takagi M, Li CL, Perbal B, Katsube K (2002) The nephroblastoma overexpressed gene (NOV/ccn3) protein associates with Notch1 extracellular domain and inhibits myoblast differentiation via Notch signaling pathway. J Biol Chem 277:29399-29405 (Pubitemid 41079223)
70. Chen C-C, Chen N, Lau LF (2001) The angiogenic factors Cyr61 and CTGF induce adhesive signaling in primary human skin fibroblasts. J Biol Chem 276:10443-10452
71. Grzeszkiewicz TM, Kirschling DJ, Chen N, Lau LF (2001) CYR61 stimulates human skin fibroblasts migration through integrin αvβ5 and enhances mitogenesis through integrin αvβ3, independent of its carboxyl-terminal domain. J Biol Chem 276:21943-21950
72. Leu S-J, Lam SCT, Lau LF (2002) Proangiogenic activities of CYR61 (CCN1) mediated through integrins αvβ3 and α6β1 in human umbilical vein endothelial cells. J Biol Chem 277:46248-46255 (Pubitemid 35417617)
73. Lin BR, Chang CC, Chen LR, Wu MH, Wang MY, Kuo IH, Chu CY, Chang KJ, Lee PH, Chen WJ et al (2007) Cysteine-rich 61 (CCN1) enhances chemotactic migration, transendothelial cell migration, and intravasation by concomitantly up-regulating chemokine receptor 1 and 2. Mol Cancer Res 5:1111-1123
74. Sun ZJ, Wang Y, Cai Z, Chen PP, Tong XJ, Xie D (2008) Involvement of Cyr61 in growth, migration, and metastasis of prostate cancer cells. Br J Cancer 99:1656-1667
75. Kassis JN, Virador VM, Guancial EA, Kimm D, Ho AS, Mishra M, Chuang EY, Cook J, Gius D, Kohn EC (2009) Genomic and phenotypic analysis reveals a key role for CCN1 (CYR61) in BAG3-modulated adhesion and invasion. J Pathol 218:495-504
76. Sakamoto S, Yokoyama M, Aoki M, Suzuki K, Kakehi Y, Saito Y (2004) Induction and function of CYR61 (CCN1) in prostatic stromal and epithelial cells: CYR61 is required for prostatic cell proliferation. Prostate 61:305-317 (Pubitemid 39564275)
77. Franzen CA, Chen CC, Todorovic V, Juric V, Monzon RI, Lau LF (2009) The matrix protein CCN1 is critical for prostate carcinoma cell proliferation and TRAIL-induced apoptosis. Mol Cancer Res 7:1045-1055
78. Gery S, Xie D, Yin D, Gabra H, Miller C, Wang H, Scott D, Yi WS, Popoviciu ML, Said JW et al (2005) Ovarian carcinomas: CCN genes are aberrantly expressed and CCN1 promotes proliferation of these cells. Clin Cancer Res 11:7243-7254 (Pubitemid 41507681)
79. Zhang Q, Wu J, Cao Q, Xiao L, Wang L, He D, Ouyang G, Lin J, Shen B, Shi Y et al (2009) A critical role of Cyr61 in interleukin- 17-dependent proliferation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Rheum 60:3602-3612
80. Jin Y, Kim HP, Ifedigbo E, Lau LF, Choi AM (2005) Cyr61 protects against hyperoxia induced cell death via Akt pathway in pulmonary epithelial cells.AmJ Respir Cell Mol Biol 33:297-302 (Pubitemid 41254297)
81. Lin MT, Chang CC, Chen ST, Chang HL, Su JL, Chau YP, Kuo ML (2004) Cyr61 expression confers resistance to apoptosis in breast cancer MCF-7 cells by a mechanism of NF-κB-dependent XIAP up-regulation. J Biol Chem 279:24015-24023
82. O'Brien TP, Lau LF (1992) Expression of the growth factorinducible immediate early gene cyr61 correlates with chondrogenesis during mouse embryonic development. Cell Growth Differ 3:645-654
83. Babic AM, Kireeva ML, Kolesnikova TV, Lau LF (1998) CYR61, product of a growth factor-inducible immediate-early gene, promotes angiogenesis and tumor growth. Proc Natl Acad Sci USA 95:6355-6360 (Pubitemid 28249016)
84. Fataccioli V, Abergel V, Wingertsmann L, Neuville P, Spitz E, Adnot S, Calenda V, Teiger E (2002) Stimulation of angiogenesis by cyr61 gene: a new therapeutic candidate. Hum Gene Ther 13:1461-1470
85. Mo FE, Muntean AG, Chen CC, Stolz DB, Watkins SC, Lau LF (2002) CYR61 (CCN1) is essential for placental development and vascular integrity. Mol Cell Biol 22:8709-8720 (Pubitemid 35397184)
86. Mo F-E, Lau LF (2006) The matricellular protein CCN1 is essential for cardiac development. Circ Res 99:961-969 (Pubitemid 44657799)
87. Chen C-C, Mo F-E, Lau LF (2001) The angiogenic inducer Cyr61 induces a genetic program for wound healing in human skin fibroblasts. J Biol Chem 276:47329-47337
88. Grote K, Salguero G, Ballmaier M, Dangers M, Drexler H, Schieffer B (2007) The angiogenic factor CCN1 promotes adhesion and migration of circulating CD34 ? progenitor cells: potential role in angiogenesis and endothelial regeneration. Blood 110:877-885 (Pubitemid 47267424)
89. Wong M, Kireeva ML, Kolesnikova TV, Lau LF (1997) Cyr61, product of a growth factor-inducible immediate-early gene, regulates chondrogenesis in mouse limb bud mesenchymal cells. Dev Biol 192:492-508 (Pubitemid 28066950)
90. Si W, Kang Q, Luu HH, Park JK, Luo Q, Song WX, Jiang W, Luo X, Li X, Yin H et al (2006) CCN1/Cyr61 is regulated by the canonical Wnt signal and plays an important role in Wnt3Ainduced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol 26:2955-2964
91. Crockett JC, Schutze N, Tosh D, Jatzke S, Duthie A, Jakob F, Rogers MJ (2007) The matricellular protein CYR61 inhibits osteoclastogenesis by a mechanism independent of αvβ3 and αvβ5. Endocrinology 148:5761-5768 (Pubitemid 350146182)
92. Su JL, Chiou J, Tang CH, Zhao M, Tsai CH, Chen PS, Chang YW, Chien MH, Peng CY, Hsiao M et al (2010) CYR61 regulates BMP-2-dependent osteoblast differentiation through the αvβ3 integrin/integrin-linked kinase/ERK pathway. J Biol Chem 285:31325-31336
93. Tamura I, Rosenbloom J, Macarak E, Chaqour B (2001) Regulation of Cyr61 gene expression by mechanical stretch through multiple signaling pathways. Am J Physiol Cell Physiol 281:C1524-C1532
94. Sabbah M, Prunier C, Ferrand N, Megalophonos V, Lambein K, De WO, Nazaret N, Lachuer J, Dumont S, Redeuilh G (2011) CCN5, a novel transcriptional repressor of transforming growth factor-β signaling pathway. Mol Cell Biol 31:1459-1469
95. Gellhaus A, Schmidt M, Dunk C, Lye SJ, Kimmig R, Winterhager E (2006) Decreased expression of the angiogenic regulators CYR61 (CCN1) and NOV (CCN3) in human placenta is associated with pre-eclampsia. Mol Hum Reprod 12:389-399 (Pubitemid 43985610)
96. Gellhaus A, Schmidt M, Dunk C, Lye SJ, Winterhager E (2007) The circulating proangiogenic factors CYR61 (CCN1) and NOV (CCN3) are significantly decreased in placentae and sera of preeclamptic patients. Reprod Sci 14:46-52
97. Sheffield VC, Pierpont ME, Nishimura D, Beck JS, Burns TL, Berg MA, Stone EM, Patil SR, Lauer RM (1997) Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis. Hum Mol Genet 6:117-121 (Pubitemid 27033974)
98. Jay P, Berge-Lefranc JL, Marsollier C, Mejean C, Taviaux S, Berta P (1997) The human growth factor-inducible immediate early gene, CYR61, maps to chromosome 1p. Oncogene 14:1753-1757 (Pubitemid 27198948)
99. Latinkic BV, Mercurio S, Bennett B, Hirst EM, Xu Q, Lau LF, Mohun TJ, Smith JC (2003) Xenopus Cyr61 regulates gastrulation movements and modulates Wnt signalling. Development 130:2429-2441 (Pubitemid 36722394)
100. Mongiat M, Ligresti G, Marastoni S, Lorenzon E, Doliana R, Colombatti A (2007) Regulation of the extrinsic apoptotic pathway by the extracellular matrix glycoprotein EMILIN2. Mol Cell Biol 27:7176-7187 (Pubitemid 47549753)
101. Chen CC, Lau LF (2010) Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines. J Cell Commun Signal 4:63-69
102. Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745-756 (Pubitemid 41070815)
103. Locksley RM, Killeen N, Lenardo MJ (2001) The TNF and TNF receptor superfamilies: integrating mammalian biology. Cell 104:487-501 (Pubitemid 32201945)
104. Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120:649-661 (Pubitemid 40343077)
105. Chang L, Kamata H, Solinas G, Luo JL, Maeda S, Venuprasad K, Liu YC, Karin M (2006) The E3 ubiquitin ligase itch couples JNK activation to TNFα-induced cell death by inducing c-FLIP(L) turnover. Cell 124:601-613 (Pubitemid 43199444)
106. Juric V, Chen CC, Lau LF (2009) Fas-mediated apoptosis is regulated by the extracellular matrix protein CCN1 (CYR61) in vitro and in vivo. Mol Cell Biol 29:3266-3279
107. Trautwein C, Rakemann T, Brenner DA, Streetz K, Licato L, Manns MP, Tiegs G (1998) Concanavalin A-induced liver cell damage: activation of intracellular pathways triggered by tumor necrosis factor in mice. Gastroenterology 114:1035-1045 (Pubitemid 28217571)
108. Wolf D, Hallmann R, Sass G, Sixt M, Kusters S, Fregien B, Trautwein C, Tiegs G (2001) TNF-a-induced expression of adhesion molecules in the liver is under the control of TNFR1- relevance for concanavalin A-induced hepatitis. J Immunol 166:1300-1307 (Pubitemid 32060291)
109. Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T, Nagata S (1993) Lethal effect of the anti-Fas antibody in mice. Nature 364:806-809 (Pubitemid 23261761)
110. Zhou Z, Sun X, Kang YJ (2001) Ethanol-induced apoptosis in mouse liver: Fas- and cytochrome c-mediated caspase-3 activation pathway. Am J Pathol 159:329-338 (Pubitemid 33704218)
111. Chen CC, Juric V, Lau LF (2011) The extracellular matrix protein CCN1 dictates TNFα and FasL cytotoxicity in vivo. Adv Exp Med Biol 691:595-603
112. Campisi J, d'Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729-740 (Pubitemid 47312822)
113. Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223-233 (Pubitemid 47081143)
114. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853-2868
115. Kuilman T, Peeper DS (2009) Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 9:81-94
116. Young AR, Narita M (2009) SASP reflects senescence. EMBO Rep 10:228-230
117. Singer AJ, Clark RA (1999) Cutaneous wound healing. N Engl J Med 341:738-746 (Pubitemid 29407375)
118. Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453:314-321 (Pubitemid 351693137)
119. Shaw TJ, Martin P (2009) Wound repair at a glance. J Cell Sci 122:3209-3213
120. Wynn TA (2008) Cellular and molecular mechanisms of fibrosis. J Pathol 214:199-210 (Pubitemid 351160157)
121. Stramer BM, Mori R, Martin P (2007) The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair. J Invest Dermatol 127:1009-1017 (Pubitemid 46625163)
122. Eming SA, Krieg T, Davidson JM (2007) Inflammation in wound repair: molecular and cellular mechanisms. J Invest Dermatol 127:514-525
123. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656-660 (Pubitemid 46232886)
124. Jun JI, Lau LF (2010) Cellular senescence controls fibrosis in wound healing. Aging (Albany, NY) 2:627-631
125. Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, Yee H, Zender L, Lowe SW (2008) Senescence of activated stellate cells limits liver fibrosis. Cell 134:657-667
126. Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 192:547-556
127. Hadjiargyrou M, Ahrens W, Rubin CT (2000) Temporal expression of the chondrogenic and angiogenic growth factor CYR61 during fracture repair. J Bone Miner Res 15:1014-1023 (Pubitemid 30350064)
128. Nakata E, Nakanishi T, Kawai A, Asaumi K, Yamaai T, Asano M, Nishida T, Mitani S, Inoue H, Takigawa M (2002) Expression of connective tissue growth factor/hypertrophic chondrocyte-specific gene product 24 (CTGF/Hcs24) during fracture healing. Bone 31:441-447 (Pubitemid 35175446)
129. Athanasopoulos AN, Schneider D, Keiper T, Alt V, Pendurthi UR, Liegibel UM, Sommer U, Nawroth PP, Kasperk C, Chavakis T (2007) 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 282:26746-26753 (Pubitemid 47501957)
130. Sawai K, Mukoyama M, Mori K, Kasahara M, Koshikawa M, Yokoi H, Yoshioka T, Ogawa Y, Sugawara A, Nishiyama H et al (2007) Expression of CCN1 (CYR61) in developing, normal, and diseased human kidney. Am J Physiol Renal Physiol 293:F1363-F1372 (Pubitemid 47583972)
131. Cooker LA, Peterson D, Rambow J, Riser ML, Riser RE, Najmabadi F, Brigstock D, Riser BL (2007) TNF-alpha, but not IFN-gamma, regulates CCN2 (CTGF), collagen type I, and proliferation in mesangial cells: possible roles in the progression of renal fibrosis. Am J Physiol Renal Physiol 293:F157-F165 (Pubitemid 47345014)
132. Koon HW, Zhao D, Xu H, Bowe C, Moss A, Moyer MP, Pothoulakis C (2008) Substance P-mediated expression of the pro-angiogenic factor CCN1 modulates the course of colitis. Am J Pathol 173:400-410
133. Haas CS, Creighton CJ, Pi X, Maine I, Koch AE, Haines GK, Ling S, Chinnaiyan AM, Holoshitz J (2006) Identification of genes modulated in rheumatoid arthritis using complementary DNA microarray analysis of lymphoblastoid B cell lines from diseasediscordant monozygotic twins. Arthr Rheum 54:2047-2060 (Pubitemid 44051060)
134. Kok SH, Hou KL, Hong CY, Wang JS, Liang PC, Chang CC, Hsiao M, Yang H, Lai EH, Lin SK (2011) Simvastatin inhibits cytokine-stimulated Cyr61 expression in osteoblastic cells: a therapeutic benefit for arthritis. Arthr Rheum 63:1010-1020
135. Sigala F, Georgopoulos S, Papalambros E, Chasiotis D, Vourliotakis G, Niforou A, Kotsinas A, Kavantzas N, Patsouris E, Gorgoulis VG et al (2006) Heregulin, cysteine rich-61 and matrix metalloproteinase 9 expression in human carotid atherosclerotic plaques: relationship with clinical data. Eur J Vasc Endovasc Surg 32:238-245 (Pubitemid 44204108)
136. Lee HY, Chung JW, Youn SW, Kim JY, Park KW, Koo BK, Oh BH, Park YB, Chaqour B, Walsh K et al (2007) 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 100:372-380
137. Matsumae H, Yoshida Y, Ono K, Togi K, Inoue K, Furukawa Y, Nakashima Y, Kojima Y, Nobuyoshi M, Kita T et al (2008) CCN1 knockdown suppresses neointimal hyperplasia in a rat artery balloon injury model. Arterioscler Thromb Vasc Biol 28:1077-1083
138. Yu Y, Gao Y, Qin J, Kuang CY, Song MB, Yu SY, Cui B, Chen JF, Huang L (2010) CCN1 promotes the differentiation of endothelial progenitor cells and reendothelialization in the early phase after vascular injury. Basic Res Cardiol 105:713-724
139. Hasan A, Pokeza N, Shaw L, Lee HS, Lazzaro D, Chintala H, Rosenbaum D, Grant MB, Chaqour B (2011) 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 286:9542-9554
140. Folkman J (2006) Angiogenesis. Annu Rev Med 57:1-18 (Pubitemid 43261975)
141. Monnier Y, Farmer P, Bieler G, Imaizumi N, Sengstag T, Alghisi GC, Stehle JC, Ciarloni L, ndrejevic-Blant S, Moeckli R et al (2008) CYR61 and αvβ5 integrin cooperate to promote invasion and metastasis of tumors growing in preirradiated stroma. Cancer Res 68:7323-7331
142. Xie D, Miller CW, O'Kelly J, Nakachi K, Sakashita A, Said JW, Gornbein J, Koeffler HP (2001) Breast cancer. Cyr61 is overexpressed, estrogen-inducible, and associated with more advanced disease. J Biol Chem 276:14187-14194
143. Kok SH, Chang HH, Tsai JY, Hung HC, Lin CY, Chiang CP, Liu CM, Kuo MY (2010) Expression of Cyr61 (CCN1) in human oral squamous cell carcinoma: an independent marker for poor prognosis. Head Neck 32:1665-1673
144. Haque I, Mehta S, Majumder M, Dhar K, De A, McGregor D, Vanveldhuizen PJ, Banerjee SK, Banerjee S (2011) Cyr61/ CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis. Mol Cancer 10:8
145. Tsai MS, Hornby AE, Lakins J, Lupu R (2000) Expression and function of CYR61, an angiogenic factor, in breast cancer cell lines and tumor biopsies. Cancer Res 60:5603-5607
146. Xie D, Nakachi K, Wang H, Elashoff R, Koeffler HP (2001) Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features. Cancer Res 61:8917-8923 (Pubitemid 34013909)
147. Jiang WG, Watkins G, Fodstad O, Douglas-Jones A, Mokbel K, Mansel RE (2004) Differential expression of the CCN family members Cyr61, CTGF and Nov in human breast cancer. Endocr Relat Cancer 11:781-791 (Pubitemid 40065551)
148. O'Kelly J, Chung A, Lemp N, Chumakova K, Yin D, Wang HJ, Said J, Gui D, Miller CW, Karlan BY et al (2008) Functional domains of CCN1 (Cyr61) regulate breast cancer progression. Int J Oncol 33:59-67
149. D'Antonio KB, Toubaji A, Albadine R, Mondul AM, Platz EA, Netto GJ, Getzenberg RH (2010) Extracellular matrix associated protein CYR61 is linked to prostate cancer development. J Urol 183:1604-1610
150. Goodwin CR, Lal B, Zhou X, Ho S, Xia S, Taeger A, Murray J, Laterra J (2010) Cyr61 mediates hepatocyte growth factordependent tumor cell growth, migration, and Akt activation. Cancer Res 70:2932-2941
151. Lin MT, Zuon CY, Chang CC, Chen ST, Chen CP, Lin BR, Wang MY, Jeng YM, Chang KJ, Lee PH et al (2005) Cyr61 induces gastric cancer cell motility/invasion via activation of the integrin/nuclear factor-jB/ cyclooxygenase-2 signaling pathway. Clin Cancer Res 11:5809-5820
152. Tsai MS, Bogart DF, Castaneda JM, Li P, Lupu R (2002) Cyr61 promotes breast tumorigenesis and cancer progression. Oncogene 21:8178-8185 (Pubitemid 35454421)
153. Menendez JA, Vellon L, Mehmi I, Teng PK, Griggs DW, Lupu R (2005) A novel CYR61-triggered 'CYR61-avb3 integrin loop' regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway. Oncogene 24:761-779 (Pubitemid 40216085)
154. Vellon L, Menendez JA, Lupu R (2005) avb3 integrin regulates heregulin (HRG)-induced cell proliferation and survival in breast cancer. Oncogene 24:3759-3773 (Pubitemid 40826875)
155. Schmitt CA (2003) Senescence, apoptosis and therapy-cutting the lifelines of cancer. Nat Rev Cancer 3:286-295 (Pubitemid 37328864)
156. Lv H, Fan E, Sun S, Ma X, Zhang X, Han DM, Cong YS (2009) Cyr61 is up-regulated in prostate cancer and associated with the p53 gene status. J Cell Biochem 106:738-744
157. Tong X, Xie D, O'Kelly J, Miller CW, Muller-Tidow C, Koeffler HP (2001) Cyr61, a member of CCN family, is a tumor suppressor in non-small cell lung cancer. J Biol Chem 276:47709-47714
158. Tong X, O'Kelly J, Xie D, Mori A, Lemp N, McKenna R, Miller CW, Koeffler HP (2004) Cyr61 suppresses the growth of nonsmall- cell lung cancer cells via the β-catenin-c-myc-p53 pathway. Oncogene 23:4847-4855 (Pubitemid 38932157)
159. Feng P, Wang B, Ren EC (2008) Cyr61/CCN1 is a tumor suppressor in human hepatocellular carcinoma and involved in DNA damage response. Int J Biochem Cell Biol 40:98-109 (Pubitemid 350064578)
160. Chien W, Kumagai T, Miller CW, Desmond JC, Frank JM, Said JW, Koeffler HP (2004) Cyr61 suppresses growth of human endometrial cancer cells. J Biol Chem 279:53087-53096 (Pubitemid 40051809)
161. Dobroff AS, Wang H, Melnikova VO, Villares GJ, Zigler M, Huang L, Bar-Eli M (2009) Silencing cAMP-response element binding protein (CREB) identifies cysteine-rich protein 61 (CYR61) as a tumor suppressor gene in melanoma. J Biol Chem 284:26194-26206
162. Yoshida Y, Togi K, Matsumae H, Nakashima Y, Kojima Y, Yamamoto H, Ono K, Nakamura T, Kita T, TanakaM(2007) CCN1 protects cardiac myocytes from oxidative stress via β1 integrin- Akt pathway. Biochem Biophys Res Commun 355:611-618 (Pubitemid 46330198)
163. Tan TW, Yang WH, Lin YT, Hsu SF, Li TM, Kao ST, Chen WC, Fong YC, Tang CH (2009) Cyr61 increases migration and MMP-13 expression via αvβ3 integrin, FAK, ERK and AP-1- dependent pathway in human chondrosarcoma cells. Carcinogenesis 30:258-268