Disease relevance of CYR61

• In summary, these results suggest that CTGF, WISP-1, and CYR61 may play a role in the progression of breast cancer and might serve as a valuable tool for monitoring tumor status of breast cancer patients [1].
• These results suggest that CYR61 and CTGF may play a role in the progression of gliomas; their levels at diagnosis may have prognostic significance; and these proteins might serve as valuable targets for therapeutic intervention [2].
• Decreased expression of the angiogenic regulators CYR61 (CCN1) and NOV (CCN3) in human placenta is associated with pre-eclampsia [3].
• The expression pattern of CTGF and CYR61 in endothelial cells of vessels in situ supports a role for these molecules in normal endothelial homeostasis, as well as participating in the angiogenic process during embryonic development, placentation, tumor formation, fibrosis, and wound healing [4].
• Whereas most human tumor-derived cell lines tested express CYR61, the gastric adenocarcinoma cell line RF-1 does not [5].

High impact information on CYR61

• Members of the CCN (for CTGF, cyr61/cef10, nov) gene family encode cysteine-rich secreted proteins with roles in cell growth and differentiation [6].
• Contrary to this paradigm, we show that fibroblast adhesion to the angiogenic matrix protein CCN1 (CYR61) induces apoptosis, whereas endothelial cell adhesion to CCN1 promotes cell survival [7].
• Subsequent tests confirmed the presence of internal ribosome entry sites in the 5' noncoding regions of both Cyr61 and Pim-1 mRNAs [8].
• In addition, the mRNA encoding Cyr61, a secreted factor that can promote angiogenesis and tumor growth, was selectively mobilized into polysomes when eIF4F concentrations were reduced, although its overall abundance changed only slightly [8].
• Acting as an extracellular, matrix-associated signaling molecule, CYR61 promotes the adhesion of endothelial cells through interaction with the integrin alphaVbeta3 and augments growth factor-induced DNA synthesis in the same cell type [5].

Chemical compound and disease context of CYR61

• We also emphasize the functional significance of the molecular connection of CYR61 and its integrin receptor alpha(v)beta(3) enhancing breast cancer aggressiveness [9].
• This review examines the functional role of CYR61 in breast cancer disease, presenting evidence that CYR61 signaling may play a major role in estrogen- as well as growth factor-dependent breast cancer progression [9].
• Increased expression of CYR61, an extracellular matrix signaling protein, in human benign prostatic hyperplasia and its regulation by lysophosphatidic acid [10].
• In this study, both Cyr61 mRNA and protein were induced by the progestin, R5020, in T47D mammary adenocarcinoma cells in a dose- and time-dependent fashion [11].
• Taken together, our data suggest that in addition to its proangiogenic activity, Cyr61 may be a novel mediator of progesterone activity in enhancing growth-factor-driven tumor growth in breast cancer [11].
• PGE2 combined with hypoxic conditions increased CYR61 mRNA and protein levels synergistically, whereas the combination with TNFalpha abolished the CYR61 levels induced by hypoxia [12].

Biological context of CYR61

• First identified as the product of a growth factor-inducible immediate-early gene, CYR61 is an extracellular matrix-associated angiogenic inducer that functions as a ligand of integrin receptors to promote cell adhesion, migration, and proliferation [13].
• This unique phenotype is correlated with impaired Vegf-C expression in the allantoic mesoderm, suggesting that CYR61-regulated expression of Vegf-C plays a role in vessel bifurcation [13].
• To identify mAChR-inducible genes, we used a differential display approach and found that mAChRs rapidly induced transcription of the immediate early gene CYR61 in HEK 293 cells with a maximum expression after 1 h of receptor stimulation [14].
• These findings help to define the mechanisms by which CYR61 acts as an angiogenic regulator, provide a molecular interpretation for the loss of vascular integrity and increased apoptosis of vascular cells in Cyr61-null mice, and underscore the importance of CYR61 in the development and homeostasis of the vascular system [15].
• Here we show that CYR61 can also promote cell survival and tubule formation in human umbilical vein endothelial cells [15].

Anatomical context of CYR61

• CYR61 deficiency results in a specific defect in vessel bifurcation (nonsprouting angiogenesis) at the chorioallantoic junction, leading to an undervascularization of the placenta without affecting differentiation of the labyrinthine syncytiotrophoblasts [13].
• Stimulation of mAChRs induced CYR61 expression in primary neurons and rat brain where CYR61 mRNA was detected in cortical layers V and VI and in thalamic nuclei [14].
• While fibroblasts and endothelial cells generally expressed good levels of all three CCN proteins, highly invasive MDA MB 231 cells expressed lower levels of CTGF and Nov, but higher levels of Cyr61, than the less invasive MCF-7 [16].
• In this study, we show that purified CYR61 stimulates directed migration of human microvascular endothelial cells in culture through an alphaV beta3-dependent pathway and induces neovascularization in rat corneas [5].
• Although CYR61 mRNA was synthesized in hyperplastic epithelial cells, in many cases of BPH, CYR61 protein was detected in both the epithelial and stromal regions of BPH patient tissues [10].

Associations of CYR61 with chemical compounds

• Muscarinic acetylcholine receptors induce the expression of the immediate early growth regulatory gene CYR61 [14].
• Increased CYR61 expression was coupled to mAChRs by both protein kinase C and elevations of intracellular Ca(2+) [14].
• CYR61 is composed of four discrete structural domains that bear sequence similarities to the insulin-like growth factor-binding proteins, von Willebrand factor type C repeat, thrombospondin type 1 repeat, and a carboxyl-terminal (CT) domain that resembles cysteine knots found in some growth factors [17].
• It has been demonstrated recently that adhesion of primary skin fibroblasts to CYR61 is mediated through integrin alpha(6)beta(1) and cell surface heparan sulfate proteoglycans, resulting in adhesive signaling and up-regulation of matrix metalloproteinases 1 and 3 [17].
• We show that CYR61 encodes a 381 amino acid protein rich in cysteine and proline residues that is strongly conserved with the mouse homologue [18].
• The CCN1-specific integrins alpha(M)beta(2) and alpha(V)beta(3) are expressed on CD34+ cells and CCN1 stimulated integrin-dependent signaling [19].

Regulatory relationships of CYR61

• A novel CYR61-triggered 'CYR61-alphavbeta3 integrin loop' regulates breast cancer cell survival and chemosensitivity through activation of ERK1/ERK2 MAPK signaling pathway [20].
• Cyr61 gene induction by R5020 was transcriptionally regulated by progesterone receptor (PR) as the antiprogestin, RU486, and actinomycin D blocked induction completely [11].
• In this study, we show that a CYR61 mutant (CYR61DeltaCT) that has the CT domain deleted is unable to support adhesion of primary human skin fibroblasts but is still able to stimulate chemotaxis and enhance basic fibroblast growth factor-induced mitogenesis similar to wild type [17].
• CYR61 stimulates human skin fibroblast migration through Integrin alpha vbeta 5 and enhances mitogenesis through integrin alpha vbeta 3, independent of its carboxyl-terminal domain [17].
• Taken together, our data suggested that Cyr61 plays an important role in resistance to chemotherapeutic agent-induced apoptosis in human breast cancer MCF-7 cells by a mechanism involving the activation of the integrins/NF-kappaB/XIAP signaling pathway [21].
• Knockdown of expression of the Cyr61 gene inhibited IL-17-stimulated FLS proliferation [22].

Other interactions of CYR61

• Elevated levels of connective tissue growth factor, WISP-1, and CYR61 in primary breast cancers associated with more advanced features [1].
• By contrast, in endothelial cells in which integrins are activated by phorbol ester or vascular endothelial growth factor, CYR61-promoted cell adhesion, migration, survival, growth factor-induced mitogenesis, and endothelial tubule formation are all mediated through integrin alpha(v)beta(3) [15].
• Moreover, anti-Cyr61 neutralizing antibodies reduced the synergistic effects of R5020 and EGF on T47D cell growth by 30% [11].
• The mRNA for CYR61, a growth factor-inducible immediate early gene, was markedly induced by fetal bovine serum (FBS) within 1 hr, and strongly induced by transforming growth factor-beta1 (TGF-beta) for at least 19 hr following stimulation [23].
• Elevated CYR61 caused down-regulation of transforming growth factor-beta type II receptor mRNA and protein levels, thereby impairing the transforming growth factor-beta pathway, which reduced type I procollagen and raised MMP-1 expression [24].
• Taken together, the present work demonstrates a potential paracrine loop consisting of the VEGF-mediated up-regulation of CCN1 in osteoblasts that attracts endothelial cells and promotes angiogenesis [25].

Analytical, diagnostic and therapeutic context of CYR61

• Sequence analysis reveals the presence of several distinct protein domains which confer a mosaic structure to this protein and makes human CYR61 a member of a recently described growth regulator family that includes several proto-oncogene products [18].
• Furthermore, on DNA microarray analysis for normal and BPH patients, CYR61 was found to be related to the development and progression of BPH, regardless of symptoms [10].
• Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was utilized to screen for inducers of the CYR61 gene in prostatic cells [23].
• Immunohistochemistry revealed the presence of CYR61 protein in glandular and luminal epithelial cells as well as in blood vessels of eutopic and ectopic endometrium [26].
• Northern blot further confirmed the Cyr61 and CTGF up-regulation is in a dose- and time-dependent manner [27].

References