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Cited by 339Connective Tissue Growth Factor ResearchBone and Dental Protein StudiesBiomarkers in Disease Mechanisms

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

Open access
Lau, Lester F.·2011·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-011-0778-3PMC PMC3651699
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Abstract

CCN1 (CYR61) is a dynamically expressed, multifunctional matricellular protein that plays essential roles in cardiovascular development during embryogenesis, and regulates inflammation, wound healing and fibrogenesis in the adult. Aberrant CCN1 expression is associated with myriad pathologies, including various cancers and diseases associated with chronic inflammation. CCN1 promotes diverse and sometimes opposing cellular responses, which can be ascribed, as least in part, to disparate activities mediated through its direct binding to distinct integrins in different cell types and contexts. Accordingly, CCN1 promotes cell proliferation, survival and angiogenesis by binding to integrin αvβ3, and induces apoptosis and senescence through integrin α6β1 and heparan sulfate proteoglycans. The ability of CCN1 to trigger the accumulation of a robust and sustained level of reactive oxygen species underlies some of its unique activities as a matrix cell-adhesion molecule. Emerging studies suggest that CCN1 might be useful as a biomarker or therapeutic target in certain diseases.

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Crossref · 10.1007/s00018-011-0778-3

Cites

168 of 168 references verified0 citation errors · 0 not checkable

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Claims the paper makes

0 of 274 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    CCN1 induces apoptosis and senescence through integrin α6β1 and heparan sulfate proteoglycans.

    “induces apoptosis and senescence through integrin α6β1 and heparan sulfate proteoglycans”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • Premisenone given

    Abnormal CCN1 expression is linked to many diseases, including cancers and chronic inflammatory conditions.

    “Aberrant CCN1 expression is associated with myriad pathologies, including various cancers and diseases associated with chronic inflammation.”
    Quote in the paperNot a substantial claim
  • Interpretationcitation

    CCN1's ability to cause robust and sustained reactive oxygen species accumulation underlies some of its unique activities as a matrix cell-adhesion molecule.

    “The ability of CCN1 to trigger the accumulation of a robust and sustained level of reactive oxygen species underlies some of its unique activities as a matrix cell-adhesion molecule.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • Interpretationcitation

    CCN1's varied and sometimes opposite cellular effects are due at least partly to different activities mediated by direct binding to distinct integrins in different cell types and contexts.

    “can be ascribed, as least in part, to disparate activities mediated through its direct binding to distinct integrins in different cell types and contexts”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • Premisecitation

    CCN1 is required for cardiovascular development in embryos.

    “plays essential roles in cardiovascular development during embryogenesis”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

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    • cites [86] Mo F-E, Lau LF (2006) The matricellular protein CCN1 is essential for cardiac development. Circ Res 99:961–969 source

      Not checked in the free run.

  • May combine two claims. 67
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Premisecitation

    CCN1 is a matricellular protein that is dynamically expressed and has multiple functions.

    “CCN1 (CYR61) is a dynamically expressed, multifunctional matricellular protein”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] Bornstein P (1995) Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J Cell Biol 130:503–506 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    CCN1 might be useful as a biomarker or therapeutic target in certain diseases.

    “Emerging studies suggest that CCN1 might be useful as a biomarker or therapeutic target in certain diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In adults, CCN1 controls inflammation, wound healing, and fibrogenesis.

    “regulates inflammation, wound healing and fibrogenesis in the adult”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [3] Kyriakides TR, Bornstein P (2003) Matricellular proteins as modulators of wound healing and the foreign body response. Thromb Haemost 90:986–992 source

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    • cites [4] Chiodoni C, Colombo MP, Sangaletti S (2010) Matricellular proteins: from homeostasis to inflammation, cancer, and metastasis. Cancer Metastasis Rev 29:295–307 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 is tightly associated with the ECM after secretion and supports cell adhesion by directly binding integrin receptors.

    “early studies on CCN1 showed that it is tightly associated with the ECM upon secretion [13] and supports cell adhesion through direct binding to integrin receptors [14,15]”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [13] Yang GP, Lau LF (1991) Cyr61, product of a growth factor-inducible immediate early gene, is associated with the extracellular matrix and the cell surface. Cell Growth Differ 2:351–357

      Not checked in the free run.

    • cites [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 source

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    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Current data establish CCN1 as essential for cardiovascular development during embryogenesis and critical for modulating inflammation, wound healing, and tissue repair in many adult tissues.

    “Current data have established CCN1 as being essential for cardiovascular development during embryogenesis, and critical for modulating inflammation, wound healing, and tissue repair in many tissues of the adult.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CCN1 lacks the canonical RGD sequence that binds many integrins; instead, specific non-canonical binding sites for several integrins have been identified.

    “CCN1 does not contain the canonical RGD sequence that can bind a number of integrins [54]. Instead, specific non-canonical binding sites of CCN1 for several integrins have been identified (Fig. 1) [63–66].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [54] Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–687 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Targeting CCN1 expression and signaling may hold promise for diagnostic markers and therapeutics.

    “suggesting that targeting CCN1 expression and signaling may hold promise in the development of diagnostic markers and therapeutics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Both the 5′-noncoding region of Ccn1 mRNA and a highly GC-rich region encoding part of the IGFBP domain appear to contain IRES.

    “Both the 5′-non coding region of the Ccn1 mRNA and a highly GC-rich region encoding part of the IGFBP domain appear to contain IRES [50,51].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Thrombin acts through GPCR and RhoA signaling to induce CCN1, which then interacts with integrins to promote cell proliferation, connecting GPCR and integrin signaling to enhance thrombin-induced cell proliferation.

    “Thrombin acts through the GPCR and RhoA signaling pathways to induce CCN1, which in turn interacts with integrins to promote cell proliferation [35]. Thus, CCN1 serves to connect the GPCR and integrin signaling pathways to enhance thrombin-induced cell proliferation [38].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 source

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    • cites [38] Walsh CT, Stupack D, Brown JH (2008) G protein-coupled receptors go extracellular: RhoA integrates the integrins. Mol Interv 8:165–173 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 is induced by bacterial and viral infections and by inflammatory cytokines such as IL-1 and TNF-α.

    “CCN1 is also induced by bacterial and viral infections [29–32], and by inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor α (TNF-α) [33].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [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 source

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    • cites [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 source

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    • cites [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 source

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    • cites [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 source

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    • cites [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 source

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  • May combine two claims.

    Premisecitation

    CCN1 binds HSPGs with high affinity, which serve as co-receptors with integrins in some contexts; syndecan-4 is the critical HSPG for CCN1 functions where examined.

    “CCN1 binds HSPGs with high affinity, which serve as co-receptors with integrins in some contexts [13,55]. Where examined, syndecan-4 has been identified as the HSPG critical for CCN1 functions [61,62].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [13] Yang GP, Lau LF (1991) Cyr61, product of a growth factor-inducible immediate early gene, is associated with the extracellular matrix and the cell surface. Cell Growth Differ 2:351–357

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 supports cell adhesion by binding integrins α6β1 and HSPGs in fibroblasts and smooth muscle cells, αIIbβ3 in activated platelets, αMβ2 in monocytes and macrophages, and αDβ2 in macrophage foam cells.

    “Subsequent studies have shown that CCN1 supports cell adhesion by binding integrins α6β1 and HSPGs in fibroblasts and smooth muscle cells [55,56], αIIbβ3 in activated platelets [57], αMβ2 in monocytes and macrophages [58,59], and αDβ2 in macrophage foam cells [60].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

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    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Another alternative splicing event retains intron 3, resulting in two stop codons that would terminate CCN1 within the central hinge region; this splicing is blocked under hypoxia in breast cancer cells, leading to full-length CCN1.

    “Another alternative splicing event retains intron 3, resulting in two stop codons that would terminate the CCN1 polypeptide within the central hinge region. However, this alternative splicing is blocked under hypoxic conditions in breast cancer cells, leading to the synthesis of full-length CCN1 [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mechanical stretch induction of CCN1 in human smooth muscle cells involves RhoA activation, actin remodeling, and recruitment of MRTF-A to the SRE of the CCN1 promoter.

    “Mechanical stretch induction of CCN1 in human smooth muscle cells involves activation of the RhoA GTPase, which promotes actin remodeling and consequently recruitment of the transcription factor myocardin-related transcriptional activator (MRTF-A), a G-actin-binding SRF co-activator, to the SRE of the CCN1 promoter [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    CCN1 promotes cell survival yet triggers apoptosis, enhances cell proliferation but also induces cell-cycle arrest, and promotes tumor growth yet suppresses tumorigenesis in various contexts.

    “It promotes cell survival and yet triggers apoptosis, enhances cell proliferation but also induces cell-cycle arrest, and promotes tumor growth and yet suppresses tumorigenesis in various contexts.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CCN1 is an immediate-early gene expressed at very low levels in quiescent fibroblasts and is transcriptionally activated within minutes by serum growth factors without requiring new protein synthesis.

    “CCN1 is an immediate-early gene expressed at a very low level in quiescent fibroblasts, but is transcriptionally activated within minutes of stimulation by serum growth factors without requiring de novo protein synthesis [5,6].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 source

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    • cites [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 source

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  • May combine two claims.

    Interpretationcitation

    CCN1 stimulates osteoblast differentiation through an αvβ3/ILK-dependent pathway but inhibits osteoclastogenesis, suggesting it is a bifunctional regulator of bone remodeling that promotes bone formation and inhibits bone resorption.

    “Moreover, CCN1 stimulates osteoblast differentiation through an αvβ3/ILK-dependent pathway but inhibits osteoclastogenesis, suggesting its role as a bifunctional regulator of bone remodeling that promotes bone formation but inhibits bone resorption [90–92].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 Wnt3A-induced osteoblast differentiation of mesenchymal stem cells. Mol Cell Biol 26:2955–2964 source

      Not checked in the free run.

    • cites [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 source

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    • cites [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 source

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  • May combine two claims.

    Interpretationreasoning

    This activity may contribute to CCN1's ability to promote growth factor-induced proliferation in PC3 prostate cancer cells and ovarian carcinoma cells, and IL-17-stimulated proliferation in synoviocytes.

    “This activity may contribute to its ability to promote growth factor-induced poliferation in PC3 prostate cancer cells [76,77] and ovarian carcinoma cells [78], and IL-17-stimulated proliferation in synoviocytes [79].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 source

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    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Purified CCN1 protein accelerated differentiation of mouse limb bud mesenchymal cells from E10 embryos, enhanced the extent of differentiation, and lowered the threshold cell density for differentiation.

    “purified CCN1 protein accelerated the differentiation of mouse limb bud mesenchymal cells isolated from E10 embryos, enhanced the extent of differentiation, and lowered the threshold cell density for differentiation [89].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ccn1-null mice are defective in placental vessel bifurcation and suffer severe cardiovascular defects.

    “Consistent with an important role for CCN1 in angiogenesis in vivo, Ccn1-null mice are defective in placental vessel bifurcation and suffer severe cardiovascular defects [85,86].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [86] Mo F-E, Lau LF (2006) The matricellular protein CCN1 is essential for cardiac development. Circ Res 99:961–969 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Different CCN1 molecules can separately bind distinct integrins on the same cell and generate signaling events that converge inside the cell to produce a specific biological outcome.

    “This observation suggests that different CCN1 molecules can separately bind distinct integrins on the same cell and generate signaling events that converge inside the cell to produce specific biological outcome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In human skin fibroblasts, CCN1 supports cell adhesion through α6β1-HSPGs and results in focal adhesion complexes, activation of FAK, paxillin and Rac, actin reorganization, and formation of filopodia and lamellipodia.

    “In human skin fibroblasts, CCN1 supports cell adhesion through α6β1–HSPGs and results in the formation of focal adhesion complexes, activation of focal adhesion kinase, paxillin and Rac, actin cytoskeleton reorganization, and formation of structures critical for cell motility such as filopodia and lamellipodia [70].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 does not induce DNA synthesis alone but synergizes with other mitogenic growth factors to augment growth factor-induced DNA synthesis in fibroblasts and endothelial cells through integrin αvβ3.

    “Although CCN1 does not induce DNA synthesis on its own, it can synergize with other mitogenic growth factors to augment growth factor-induced DNA synthesis in both fibroblasts and endothelial cells through integrin αvβ3 [14,71].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    These observations suggest the possibility that CCN1 may bind DNA and regulate transcription under certain conditions.

    “Although the functional implications of these observations have not been investigated further, they suggest the intriguing possibility that CCN1 may bind DNA and regulate transcription under certain conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Distinct integrin-binding sites of CCN1 can function independently: disrupting α6β1-binding sites abolishes α6β1-dependent activities without affecting αvβ3-mediated functions, and disrupting the αvβ3-binding site abolishes αvβ3- but not α6β1-mediated activities.

    “CCN1 mutants that disrupt its α6β1-binding sites abolish α6β1-dependent activities without affecting αvβ3-mediated functions [66]. Likewise, disruption of the CCN1 αvβ3-binding site abolishes αvβ3-but not α6β1-mediated activities [65].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 stimulates integrin-dependent recruitment of CD34+ progenitor cells, enhancing endothelial proliferation and neovascularization.

    “Furthermore, CCN1 stimulates the integrin-dependent recruitment of CD34+ progenitor cells, thereby enhancing endothelial proliferation and neovascularization [88].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 source

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  • May combine two claims.

    Premisecitation

    CCN1 has potent angiogenic activity, first demonstrated in a corneal micropocket implant assay and confirmed in a rabbit ischemic hindlimb model.

    “Indeed, CCN1 has potent angiogenic activity, first demonstrated in a corneal micropocket implant assay [83] and subsequently confirmed in a rabbit ischemic hindlimb model [84].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1's synergism with TNFα requires interaction with both αvβ5 and α6β1; mutants defective for either binding are incapable of functional synergism, but combining the two mutants reconstitutes wild-type activity.

    “However, the synergism of CCN1 with TNFα (see below) requires its interaction with both αvβ5 and α6β1. Interestingly, whereas CCN1 mutants defective for either binding αvβ5 or α6β1 are each incapably of functional synergism with TNFα, a combination of these two mutants can fully reconstitute wild-type activity [62].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recombinant CCN1 binds DNA with sequence specificity in vitro, and co-transfection of CCN1 expression plasmids inhibited transcription from HIV-1 LTR reporter constructs.

    “Furthermore, recombinant CCN1 was shown to bind DNA with sequence specificity in vitro, and co-transfection of CCN1 expression plasmids inhibited transcription from HIV-1 long terminal repeat reporter constructs [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 promotes endothelial cell survival through integrin αvβ3 and inhibits apoptosis by activating Akt in pulmonary epithelial cells or upregulating XIAP in MCF7 breast cancer cells.

    “CCN1 promotes the survival of endothelial cells through integrin αvβ3 [72], and inhibits apoptosis by activation of Akt in pulmonary epithelial cells [80] or upregulation of XIAP in MCF7 breast cancer cells [81].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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. Am J Respir Cell Mol Biol 33:297–302 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A short CCN1 peptide containing the α6β1-HSPG binding sites is sufficient to support cell adhesion and recapitulate sustained ERK activation by immobilized CCN1.

    “A short CCN1 peptide containing the α6β1–HSPG binding sites is sufficient to support cell adhesion and recapitulate the sustained activation of extracellular signal-regulated kinase (ERK) by immobilized CCN1 [66].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CCN1 was identified in an expression screen of a λgt11 library for proteins binding the HIV-1 long terminal repeat.

    “Interestingly, CCN1 was identified in an expression screening of a λgt11 library for proteins that bind the human immunodeficiency virus type 1 (HIV-1) long terminal repeat [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 supports cell adhesion and induces adhesive signaling in many adherent cell types.

    “This observation led to the finding that CCN1 can support cell adhesion and induce adhesive signaling in many adherent cell types [18,53].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Chen C–C, Lau LF (2009) Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol 41:771–783 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ccn1 expression during mouse embryogenesis is tightly associated with development of skeletal, cardiovascular, and neuronal systems, and targeted disruption of Ccn1 in mice results in embryonic lethality.

    “Ccn1 expression during mouse embryogenesis is tightly associated with development of the skeletal, cardiovascular, and neuronal systems [82], and targeted disruption of Ccn1 in mice results in embryonic lethality.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [82] O’Brien TP, Lau LF (1992) Expression of the growth factor-inducible immediate early gene cyr61 correlates with chondrogenesis during mouse embryonic development. Cell Growth Differ 3:645–654

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [86] Mo F-E, Lau LF (2006) The matricellular protein CCN1 is essential for cardiac development. Circ Res 99:961–969 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The human CCN1 gene and AVSD1 both map within the same chromosomal location at 1p21-31, suggesting that CCN1 may be a candidate gene for human AVSD.

    “The human CCN1 gene and AVSD1 both map within the same chromosomal location at 1p21–31 [97,98], suggesting that CCN1 may be a candidate gene for human AVSD.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Trophoblast differentiation and syncytiotrophoblast formation at the chorionic plate occur normally in the Ccn1-null placenta, forming the trilaminar trophoblast barrier; therefore the labyrinthine vascular deficiency in Ccn1-null mice is not due to trophoblast defects.

    “However, trophoblast differentiation and syncytiotrophoblast formation at the chorionic plate occur normally in the Ccn1-null placenta, forming the trilaminar trophoblast barrier between fetal vessels and maternal blood sinuses where fetal vessels are found. Therefore, the labyrinthine vascular deficiency in Ccn1-null mice is not due to trophoblast defects.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Ccn1 is also highly expressed in the developing neuronal system; however, its role in this context has not been thoroughly investigated.

    “Ccn1 is also highly expressed in the developing neuronal system; however, its role in this context has not been thoroughly investigated.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] O’Brien TP, Lau LF (1992) Expression of the growth factor-inducible immediate early gene cyr61 correlates with chondrogenesis during mouse embryonic development. Cell Growth Differ 3:645–654

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Approximately 30% of Ccn1-null embryos fail to form chorioallantoic fusion at E8.5 and die by E9.5, whereas the remaining embryos perish at mid-gestation from placental vascular insufficiency, loss of embryonic vascular integrity, hemorrhage, and severe AVSD.

    “Approximately 30% of Ccn1-null embryos fail to form chorioallantoic fusion at E8.5 and die by E9.5, whereas the remaining embryos perish at mid-gestation from placental vascular insufficiency, loss of embryonic vascular integrity, hemorrhage, and severe cardiac atrioventricular septal defect (AVSD) [85,86].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [86] Mo F-E, Lau LF (2006) The matricellular protein CCN1 is essential for cardiac development. Circ Res 99:961–969 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    At E8.5, Ccn1 is highly expressed in the ectoplacental cone and trophoblastic giant cells, suggesting a role in implantation and interaction with the decidua.

    “At E8.5, Ccn1 is highly expressed in the ectoplacental cone and in trophoblastic giant cells, suggesting a role in implantation and interaction with the decidua [82].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] O’Brien TP, Lau LF (1992) Expression of the growth factor-inducible immediate early gene cyr61 correlates with chondrogenesis during mouse embryonic development. Cell Growth Differ 3:645–654

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although CCN1 is a cell-adhesion molecule, these activities are observed when CCN1 is presented to cells either as an adhesion substrate or as a soluble factor.

    “Although CCN1 is a cell-adhesion molecule, these activities are observed when CCN1 is presented to cells either as an adhesion substrate or as a soluble factor.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although Ccn1 is prominently expressed in the skeletal system during embryogenesis, Ccn1-null mice succumb too early in development for its role in skeletal development to be assessed fully.

    “Although Ccn1 is prominently expressed in the skeletal system during embryogenesis [82], Ccn1-null mice succumb too early in development for its role in skeletal development to be assessed fully [85].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [82] O’Brien TP, Lau LF (1992) Expression of the growth factor-inducible immediate early gene cyr61 correlates with chondrogenesis during mouse embryonic development. Cell Growth Differ 3:645–654

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although Ccn1+/− mice are largely viable, they exhibit persistent ostium primum atrial septal defects with 20% penetrance.

    “Although Ccn1+/− mice are largely viable, they exhibit persistent ostium primum atrial septal defects with 20% penetrance [86].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Mo F-E, Lau LF (2006) The matricellular protein CCN1 is essential for cardiac development. Circ Res 99:961–969 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Despite normal vasculogenesis in Ccn1-null mice, specific angiogenic defects occur: vessel bifurcation is impaired in the chorionic plate, resulting in few sprouting vessels penetrating the labyrinth and an undervascularized placenta.

    “Despite normal vasculogenesis in Ccn1-null mice, specific angiogenic defects are observed. Vessel bifurcation is impaired in the chorionic plate of Ccn1-null embryos, resulting in a dearth of sprouting vessels that penetrate into the labyrinth, and thus an undervascularized placenta [85].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This finding is consistent with a role for CCN1 in placental angiogenesis and decidual tissue remodeling, and evidence suggests serum CCN1 levels may serve as a marker for early diagnosis of pre-eclampsia.

    “This finding is consistent with a role for CCN1 in placental angiogenesis and decidual tissue remodeling, and evidence suggests that serum levels of CCN1 may serve as a marker for early diagnosis of pre-eclampsia [96].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Either overexpression of CCN1 by injection of Ccn1 RNA or CCN1 knockdown by antisense morpholino oligonucleotides caused defects in gastrulation, resulting in severe delay of blastopore closure.

    “Either overexpression of CCN1 by injection of Ccn1 RNA or CCN1 knockdown by antisense morpholino oligonucleotides caused defects in gastrulation, resulting in severe delay of blastopore closure.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Ventral injection of Ccn1 mRNA induces secondary axis formation in Xenopus and activates Wnt/β-catenin signaling, but can also inhibit Wnt8-induced secondary axis formation, indicating that CCN1 can stimulate or inhibit Wnt signaling in a context-dependent manner.

    “Ventral injection of Ccn1 mRNA induces secondary axes formation in Xenopus and activates Wnt/β-catenin signaling, but can also inhibit Wnt8-induced secondary axis formation, indicating that CCN1 can stimulate or inhibit Wnt signaling in a context-dependent manner [99].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Although CCN1 promotes cell survival in endothelial cells and some cancer cells, it represents the first example of an ECM molecule that can induce apoptosis through cell adhesion.

    “Although CCN1 promotes cell survival in endothelial cells and some cancer cells [72,81], it represents the first example of an ECM molecule that can induce apoptosis through the process cell adhesion [61].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This apoptotic effect is relatively modest in normal fibroblasts but greatly enhanced in cells defective for p21, which are more susceptible to apoptotic signals.

    “This effect is relatively modest in normal fibroblasts, but is greatly enhanced in cells that are defective for p21 and are thus more susceptible to apoptotic signals.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Human AVSD is a common group of congenital disorders often associated with Down syndrome, whereas non-syndromic AVSDs are typically inherited with autosomal dominance.

    “Human AVSD is a common group of congenital disorders often associated with Down’s syndrome, whereas non-syndromic AVSDs are typically inherited with autosomal dominance [97].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TNF-α is a pro-inflammatory cytokine and a potent activator of NF-κB, which induces many pro-mitogenic, pro-inflammatory, and anti-apoptotic proteins, promoting cell proliferation and survival.

    “TNF-α is a pro-inflammatory cytokine and a potent activator of the transcription factor NF-κB, which induces the expression of a multitude of pro-mitogenic, pro-inflammatory, and anti-apoptotic proteins, thus promoting cell proliferation and survival [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 3:745–756 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fas-mediated apoptosis is also reduced, as judged by using the monoclonal antibody Jo2 that recognizes and activates the Fas receptor and induces hepatic apoptosis, or by using ethanol gavage in mice, a system that mimics binge drinking in humans and triggers FasL-induced hepatocyte apoptosis.

    “Fas-mediated apoptosis is also reduced, as judged by using the monoclonal antibody Jo2 that recognizes and activates the Fas receptor and induces hepatic apoptosis [109], or by using ethanol gavage in mice, a system that mimics binge drinking in humans and triggers FasL-induced hepatocyte apoptosis [110].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Adhesion to CCN1 produces higher and more sustained ROS than adhesion to collagen, fibronectin, or laminin, which do not induce senescence.

    “Cell adhesion to CCN1 induces a much higher and more sustained level of ROS than cell adhesion to other ECM proteins such as collagen, fibronectin, and laminin, which do not induce senescence.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    CCN1 converts ECM-synthesizing myofibroblasts into ECM-degrading senescent cells, limiting fibrogenesis and promoting wound resolution.

    “Hence, CCN1 turns the ECM-synthesizing myofibroblasts themselves into ECM-degrading senescent cells, thereby imposing a self-limiting effect on fibrogenesis and promoting wound resolution (Fig. 3) [124].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] Jun JI, Lau LF (2010) Cellular senescence controls fibrosis in wound healing. Aging (Albany, NY) 2:627–631 source

      Not checked in the free run.

    • Rests on an assumption: Senescent myofibroblasts no longer proliferate, which reduces the number of ECM-producing cells.

  • May combine two claims.

    Premisecitation

    NOX1, but not 5-lipoxygenase, is specifically required for CCN1-induced senescence.

    “Although CCN1 induces ROS through several pathways, NOX1, but not 5-lipoxygenase, is specifically required for the induction of senescence [2].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells express the SASP, marked by increased ECM-degrading enzymes such as MMPs, inflammatory cytokines/chemokines, and reduced ECM components such as collagen.

    “An important feature of senescent cells is the expression of the senescence-associated secretory phenotype (SASP), characterized by the increased expression of ECM-degrading enzymes such as matrix metalloproteinases (MMPs), inflammatory cytokines/chemokines, and down-regulation of ECM components such as collagen [112,114–116].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [115] Kuilman T, Peeper DS (2009) Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 9:81–94 source

      Not checked in the free run.

    • cites [116] Young AR, Narita M (2009) SASP reflects senescence. EMBO Rep 10:228–230 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both p53 and p16INK4a/pRb pathways activated by CCN1 contribute to cellular senescence induction.

    “Both p53 and p16INK4a/pRb pathways, which are activated by CCN1, contribute to the induction of cellular senescence [112,113].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [113] Collado M, Blasco MA, Serrano M (2007) Cellular senescence in cancer and aging. Cell 130:223–233 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Senescent cells express an anti-fibrotic SASP that upregulates MMPs and downregulates collagen, leading to matrix degradation.

    “Second, senescent cells express the anti-fibrotic SASP as described above, upregulating MMPs and downregulating collagen expression, leading to matrix degradation [2,70].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1-induced senescent fibroblasts express elevated MMPs and downregulate collagen and TGF-β1, producing a matrix-degrading phenotype.

    “Consistently, CCN1-induced senescent fibroblasts express elevated levels of MMPs and downregulate collagen and TGF-β1, thus imposing a matrix-degrading phenotype [2].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In contrast to the embryonic lethality of Ccn1-null mice, these knockin mice are viable, fertile, and do not exhibit any obvious developmental defects.

    “In contrast to the embryonic lethality of Ccn1-null mice, these knockin mice are viable, fertile, and do not exhibit any obvious developmental defects.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Topical application of purified CCN1 protein to cutaneous wounds reverses the defects and supports a critical role for CCN1 in controlling myofibroblast senescence to limit fibrosis.

    “Topical application of purified CCN1 protein to cutaneous wounds reverses these defects, further establishing the critical role of CCN1 in controlling myofibroblast senescence to limit fibrosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In knockin mice with a CCN1 mutant unable to bind α6β1-HSPGs and defective for senescence induction, senescent cells do not accumulate in granulation tissue during wound healing, resulting in exacerbated fibrosis.

    “In knockin mice that express a CCN1 mutant unable to bind α6β1–HSPGs and are thus defective for the induction of senescence, senescent cells do not accumulate in the granulation tissue during wound healing, resulting in exacerbated fibrosis [2].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 promotes tumor growth and increases tumor vascularization when overexpressed in human gastric adenocarcinoma cells in SCID mice.

    “With the discovery of its angiogenic activity, CCN1 was shown to promote tumor growth and increase tumor vascularization when overexpressed in human gastric adenocarcinoma cells in SCID mice [83].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 can promote cancer cell proliferation, invasion, survival, and metastasis.

    “In addition to angiogenesis, CCN1 can also promote cancer cell proliferation, invasion, survival, and metastasis [74,75,141].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 can recruit CD34+ endothelial progenitor cells to the endothelial monolayer and promote their differentiation.

    “Overexpression of CCN1 from an adenoviral vector accelerates re-endothelialization after balloon injury, possibly because CCN1 can recruit CD34+ endothelial progenitor cells to the endothelial monolayer and promote their differentiation [88,138].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CCN1 can play important roles in inflammation, in part by acting on inflammatory cells such as macrophages, inducing angiogenesis, and collaborating with cytokines such as TNF-α.

    “These findings suggest that CCN1 can play important roles in inflammation, in part by acting on inflammatory cells such as macrophages, inducing angiogenesis, and collaborating with cytokines such as TNF-α.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Forced expression of CCN1 enhanced tumor growth in xenografts of breast cancer cells, prostate cancer cells, ovarian carcinoma cells, and squamous carcinoma cells.

    “Accordingly, subsequent studies have shown that forced expression of CCN1 enhanced tumor growth in xenografts of breast cancer cells [142], prostate cancer cells [74], ovarian carcinoma cells [78], and squamous carcinoma cells [143].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CCN1 expression significantly correlates with stage, tumor size, lymph node positivity, and poor prognosis in several cancers, including breast cancer, prostate cancer, glioma, gastric adenocarcinoma, and squamous cell carcinoma.

    “The clinical relevance of these observations is supported by the finding of a significant correlation between CCN1 expression and the stage, tumor size, lymph node positivity, and poor prognosis in several cancers, including breast cancer [142,145–148], prostate cancer [149], glioma [150], gastric adenocarcinoma [151], and squamous cell carcinoma [143].”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [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 source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

    • cites [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 source

      Not checked in the free run.

    • cites [150] Goodwin CR, Lal B, Zhou X, Ho S, Xia S, Taeger A, Murray J, Laterra J (2010) Cyr61 mediates hepatocyte growth factor-dependent tumor cell growth, migration, and Akt activation. Cancer Res 70:2932–2941 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In adults, CCN1 plays critical roles in inflammation, wound healing, and tissue repair, and is aberrantly expressed in many diseases associated with deregulation of these processes.

    “In addition to these developmental functions, in the adult it plays critical roles in inflammation, wound healing, and tissue repair, and is aberrantly expressed in myriad diseases associated with deregulation of these processes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    High levels of CCN1 expression are found in prostate cancer cell lines with mutant or null p53, while lower levels are found in cells expressing wild-type p53.

    “Interestingly, high levels of CCN1 expression are found in prostate cancer cell lines with a mutant or null p53 gene, but lower levels are found in cells expressing wild-type p53 [156].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The role of CCN1 in tumorigenesis may be cell type- and context-dependent, and may depend on whether cells are susceptible to CCN1-induced apoptosis or senescence, or whether angiogenic factors are limiting.

    “Thus, the role of CCN1 in tumorigenesis may be cell type- and context-dependent, and may hinge on whether the cell types are susceptible to CCN1-induced apoptosis or senescence, or whether angiogenic factors are limiting.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CCN1 expression in melanoma cells reduced tumor growth and metastasis and increased apoptosis in tumors.

    “and CCN1 expression in melanoma cells reduced tumor growth and metastasis and concomitantly increased apoptosis in tumors [161].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Apoptosis and cellular senescence are well-established mechanisms of tumor suppression.

    “However, CCN1 can also induce apoptosis and cellular senescence [2,61,101], two well-established mechanisms of tumor suppression [155].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] Schmitt CA (2003) Senescence, apoptosis and therapy—cutting the lifelines of cancer. Nat Rev Cancer 3:286–295 source

      Not checked in the free run.

72 of 72

  • The paper relies on this without support.

    Senescent myofibroblasts no longer proliferate, which reduces the number of ECM-producing cells.

    “First, senescent myofibroblasts no longer proliferate, thereby curbing the number of ECM-producing cells.”

  • The paper relies on this without support.

    TNF-α is critical in both inflammatory bowel disease and rheumatoid arthritis, and anti-TNF-α therapy is in clinical use for these diseases.

    “It is interesting to note that TNF-α is known to be critical in both inflammatory bowel disease and rheumatoid arthritis, and anti-TNF-α therapy is in clinical use for these diseases.”
2 of 2

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Authors
Lau, L. F.
Affiliations
University of Illinois Chicago (US)
Corresponding author
Lau, Lester F.
ORCID
Lau, Lester F.
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2011-07-31
Volume
68
Issue
19
Pages
3149-3163
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-011-0778-3
PMC
PMC3651699
OpenAlex
W1965362233
Semantic Scholar
fe1c6ae6369e97501c934d7d841390a1afaf47e6
Cited by
338
References
169
Citations by year
2026: 23 · 2025: 28 · 2024: 19 · 2023: 13 · 2022: 28 · 2021: 21 · 2020: 23 · 2019: 16 · 2018: 21 · 2017: 23 · 2016: 31 · 2015: 31 · 2014: 27 · 2013: 23 · 2012: 9
FWCI
1.74
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cellular and Molecular Life Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL081390, HL81390)
  • National Cancer Institute (R01CA046565, CA-46565)
  • National Institute of General Medical Sciences (R01GM078492, GM78492)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR061791)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connective Tissue Growth Factor Research
  • Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
  • Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
Keywords
CYR61, matricellular proteins, integrin binding, integrin αvβ3, alpha6beta1 integrin, heparan sulfate proteoglycans, angiogenesis, cell proliferation, apoptosis, cellular senescence, reactive oxygen species, wound healing, fibrosis, inflammation, cardiovascular development, cancer, biomarkers, therapeutic target
MeSH terms
Animals, Cell Adhesion, Cell Movement, DNA, Female, Gene Expression Regulation, Models, Biological, Neoplasms, Pregnancy, Receptors, Cell Surface, Wound Healing, Signal Transduction, Integrins, Cellular Senescence, Reactive Oxygen Species, Embryonic Development, Cell Proliferation, Mice, Cysteine-Rich Protein 61

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

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