Academic literature on the topic 'Fibulin-2'
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Journal articles on the topic "Fibulin-2"
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Sicot, Francois-Xavier, Takeshi Tsuda, Dessislava Markova, John F. Klement, Machiko Arita, Rui-Zhu Zhang, Te-Cheng Pan, Robert P. Mecham, David E. Birk, and Mon-Li Chu. "Fibulin-2 Is Dispensable for Mouse Development and Elastic Fiber Formation." Molecular and Cellular Biology 28, no. 3 (December 10, 2007): 1061–67. http://dx.doi.org/10.1128/mcb.01876-07.
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ABSTRACT Fibulin-2 is an extracellular matrix protein belonging to the five-member fibulin family, of which two members have been shown to play essential roles in elastic fiber formation during development. Fibulin-2 interacts with two major constituents of elastic fibers, tropoelastin and fibrillin-1, in vitro and localizes to elastic fibers in many tissues in vivo. The protein is prominently expressed during morphogenesis of the heart and aortic arch vessels and at early stages of cartilage development. To examine its role in vivo, we generated mice that do not express the fibulin-2 gene (Fbln2) through homologous recombination of embryonic stem cells. Unexpectedly, the fibulin-2-null mice were viable and fertile and did not display gross and anatomical abnormalities. Histological and ultrastructural analyses revealed that elastic fibers assembled normally in the absence of fibulin-2. No compensatory up-regulation of mRNAs for other fibulin members was detected in the aorta and skin tissue. However, in the fibulin-2 null aortae, fibulin-1 immunostaining was increased in the inner elastic lamina, where fibulin-2 preferentially localizes. The results demonstrate that fibulin-2 is not required for mouse development and elastic fiber formation and suggest possible functional redundancy between fibulin-1 and fibulin-2.
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Sasaki, T., H. Wiedemann, M. Matzner, M. L. Chu, and R. Timpl. "Expression of fibulin-2 by fibroblasts and deposition with fibronectin into a fibrillar matrix." Journal of Cell Science 109, no. 12 (December 1, 1996): 2895–904. http://dx.doi.org/10.1242/jcs.109.12.2895.
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The extracellular matrix protein fibulin-2 was shown to be a typical product of cultured human and mouse fibroblasts by several immunological assays. It is secreted and deposited in cells and tissues as a disulfide-bonded oligomer identical in size to the previously described recombinant fibulin-2. Most of the fibroblast fibulin-2 is deposited into a dense fibrillar meshwork which requires treatment with EDTA and/or 6 M urea for solubilization. Fibulin-2 and fibronectin are synthesized at equivalent levels and both colocalize in the fibrils as shown by immunofluorescence. Metabolic labelling and pulse-chase studies demonstrated fibulin-2 oligomers in detergent extracts of cells and their rapid translocation to extracellular EDTA-sensitive assembly forms. Unlike for fibronectin and fibulin-1 only a little fibulin-2 was found in the cell culture medium. Immunogold staining of confluent human fibroblasts showed localization of fibulin-2 to a fine meshwork or bundles of amorphous microfibrils in the matrix. This also demonstrated a distinct colocalization of fibulin-2 and fibronectin at the electron microscope level, indicating that the interaction between these two protein shown in in vitro assays may also exist in situ. No distinct colocalization of both proteins could, however, be observed with cross-striated fibrils of collagen I and collagen VI microfibrils.
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Pan, T. C., T. Sasaki, R. Z. Zhang, R. Fässler, R. Timpl, and M. L. Chu. "Structure and expression of fibulin-2, a novel extracellular matrix protein with multiple EGF-like repeats and consensus motifs for calcium binding." Journal of Cell Biology 123, no. 5 (December 1, 1993): 1269–77. http://dx.doi.org/10.1083/jcb.123.5.1269.
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A new protein, fibulin-2, was predicted from sequence analysis of cDNA clones obtained from a mouse fibroblast library. This protein consists of a 1195-residue polypeptide preceded by a 26-residue signal peptide. The COOH-terminal region of 787 amino acids contained three anaphylatoxin-related segments (domain I), 11 EGF-like repeats (domain II), 10 of which had a consensus motif for calcium-binding, and a 115-residue globular domain III. Except for two additional EGF-like repeats, this COOH-terminal region showed 43% sequence identity with the previously described fibulin-1 (BM-90). The NH2-terminal 408 residues, unique to fibulin-2, showed no sequence homology to other known proteins and presumably form two additional domains that differ in their cysteine content. Recombinant fibulin-2 was produced and secreted by human cell clones as a disulfide-bonded trimer. Rotary shadowing visualized the protein as three 40-45 nm long rods which are connected at one end in a globe-like structure. No significant immunological cross-reaction could be detected between fibulin-1 and fibulin-2. Production of the fibulin-2 was demonstrated by Northern blots and radioimmunoassay in fibroblasts but not in several tumor cell lines. Together with the observation that the serum level of fibulin-2 is 1,000-fold lower than that of fibulin-1, the data indicate that these two isoforms are not always coordinately expressed. This is also suggested by Northern blots of tissue mRNAs and by immunofluorescence localizations using mouse tissues. The latter studies also demonstrated an extracellular localization for fibulin-2 in basement membranes and other connective tissue compartments.
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Sofela, Agbolahan A., David A. Hilton, Sylwia Ammoun, Daniele Baiz, Claire L. Adams, Emanuela Ercolano, Michael D. Jenkinson, et al. "Fibulin-2: A Novel Biomarker for Differentiating Grade II from Grade I Meningiomas." International Journal of Molecular Sciences 22, no. 2 (January 8, 2021): 560. http://dx.doi.org/10.3390/ijms22020560.
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There is an unmet need for the identification of biomarkers to aid in the diagnosis, clinical management, prognosis and follow-up of meningiomas. There is currently no consensus on the optimum management of WHO grade II meningiomas. In this study, we identified the calcium binding extracellular matrix glycoprotein, Fibulin-2, via mass-spectrometry-based proteomics, assessed its expression in grade I and II meningiomas and explored its potential as a grade II biomarker. A total of 87 grade I and 91 grade II different meningioma cells, tissue and plasma samples were used for the various experimental techniques employed to assess Fibulin-2 expression. The tumours were reviewed and classified according to the 2016 edition of the Classification of the Tumours of the central nervous system (CNS). Mass spectrometry proteomic analysis identified Fibulin-2 as a differentially expressed protein between grade I and II meningioma cell cultures. Fibulin-2 levels were further evaluated in meningioma cells using Western blotting and Real-time Quantitative Polymerase Chain Reaction (RT-qPCR); in meningioma tissues via immunohistochemistry and RT-qPCR; and in plasma via Enzyme-Linked Immunosorbent Assay (ELISA). Proteomic analyses (p < 0.05), Western blotting (p < 0.05) and RT-qPCR (p < 0.01) confirmed significantly higher Fibulin-2 (FBLN2) expression levels in grade II meningiomas compared to grade I. Fibulin-2 blood plasma levels were also significantly higher in grade II meningioma patients compared to grade I patients. This study suggests that elevated Fibulin-2 might be a novel grade II meningioma biomarker, when differentiating them from the grade I tumours. The trend of Fibulin-2 expression observed in plasma may serve as a useful non-invasive biomarker.
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Sofela, Agbolahan A., David A. Hilton, Sylwia Ammoun, Daniele Baiz, Claire L. Adams, Emanuela Ercolano, Michael D. Jenkinson, et al. "Fibulin-2: A Novel Biomarker for Differentiating Grade II from Grade I Meningiomas." International Journal of Molecular Sciences 22, no. 2 (January 8, 2021): 560. http://dx.doi.org/10.3390/ijms22020560.
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There is an unmet need for the identification of biomarkers to aid in the diagnosis, clinical management, prognosis and follow-up of meningiomas. There is currently no consensus on the optimum management of WHO grade II meningiomas. In this study, we identified the calcium binding extracellular matrix glycoprotein, Fibulin-2, via mass-spectrometry-based proteomics, assessed its expression in grade I and II meningiomas and explored its potential as a grade II biomarker. A total of 87 grade I and 91 grade II different meningioma cells, tissue and plasma samples were used for the various experimental techniques employed to assess Fibulin-2 expression. The tumours were reviewed and classified according to the 2016 edition of the Classification of the Tumours of the central nervous system (CNS). Mass spectrometry proteomic analysis identified Fibulin-2 as a differentially expressed protein between grade I and II meningioma cell cultures. Fibulin-2 levels were further evaluated in meningioma cells using Western blotting and Real-time Quantitative Polymerase Chain Reaction (RT-qPCR); in meningioma tissues via immunohistochemistry and RT-qPCR; and in plasma via Enzyme-Linked Immunosorbent Assay (ELISA). Proteomic analyses (p < 0.05), Western blotting (p < 0.05) and RT-qPCR (p < 0.01) confirmed significantly higher Fibulin-2 (FBLN2) expression levels in grade II meningiomas compared to grade I. Fibulin-2 blood plasma levels were also significantly higher in grade II meningioma patients compared to grade I patients. This study suggests that elevated Fibulin-2 might be a novel grade II meningioma biomarker, when differentiating them from the grade I tumours. The trend of Fibulin-2 expression observed in plasma may serve as a useful non-invasive biomarker.
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Klingen, Tor A., Ying Chen, Hans Aas, Elisabeth Wik, and Lars A. Akslen. "Fibulin-2 expression associates with vascular invasion and patient survival in breast cancer." PLOS ONE 16, no. 4 (April 9, 2021): e0249767. http://dx.doi.org/10.1371/journal.pone.0249767.
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Stromal elastosis is related to good prognosis in breast cancer and fibulin-2 helps to stabilize elastic fibers in basement membranes. Here, we examined the level of perivascular fibulin-2 expression in relation to elastosis content, vascular invasion, molecular subtypes, tumour detection mode, and patient prognosis in breast cancer. We performed a population based retrospective study of invasive breast cancers from the Norwegian Breast Screening Program (Vestfold County, 2004–2009) including 200 screen-detected and 82 interval cancers. Perivascular fibulin-2 staining was semi-quantitatively graded based on immunohistochemistry (1–3) and dichotomized as high expression (grade 2–3) and low expression (grade 1). Elastosis content was graded on a 4-tiered scale and dichotomized as high (score 3) and low (score 0–2) expression, whereas lymphatic (LVI) and blood vessel invasion (BVI) were recorded as absent or present by immunohistochemistry. High perivascular fibulin-2 expression was strongly related to stromal elastosis (p<0.001), and inversely associated with BVI and LVI (p<0.001 for both). High fibulin-2 was associated with luminal breast cancer subgroups (p<0.001) and inversely with interval cancers compared with screen-detected tumours (p<0.001). By univariate analysis, low perivascular fibulin-2 was associated with reduced recurrence-free survival (p = 0.002) and disease specific survival (p = 0.019). Low perivascular fibulin-2 expression was strongly related to vascular invasion, low stromal elastosis, non-luminal breast cancer subtypes, interval presentation, and adverse prognosis.
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Cangemi, Claudia, Vibe Skov, Michael Kjaer Poulsen, Jonas Funder, Waleed O. Twal, Mari-Anne Gall, Vibeke Hjortdal, et al. "Fibulin-1 Is a Marker for Arterial Extracellular Matrix Alterations in Type 2 Diabetes." Clinical Chemistry 57, no. 11 (November 1, 2011): 1556–65. http://dx.doi.org/10.1373/clinchem.2011.162966.
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BACKGROUND Extracellular matrix alterations are important elements in the arterial changes seen in diabetes, being associated with increased vascular stiffness and the development of cardiovascular diseases. However, no biomarkers for diabetes-related arterial changes have been defined. METHODS Mammary artery specimens from 17 men with type 2 diabetes and 18 nondiabetic individuals were used for microarray expression profiling, quantitative real-time PCR, immunoassay, and immunohistochemical analyses. A derived candidate marker, fibulin-1, which is an elastin-associated matrix molecule, was measured immunochemically in plasma from (a) 70 patients scheduled for vascular surgery, (b) 305 patients with type 2 diabetes examined with carotid ultrasonography and echocardiography, and (c) 308 patients with type 2 diabetes, followed for 15 years. RESULTS The most upregulated transcript in nonatherosclerotic arterial tissue from patients with type 2 diabetes encoded the extracellular matrix protein, fibulin-1. Higher concentrations of fibulin-1-protein were present in artery extracts from patients with diabetes than extracts from individuals without diabetes, and increased fibulin-1 immunostaining was apparent around the external elastic lamina of diabetic arteries. Patients with diabetes displayed increased plasma concentrations of fibulin-1 (P = 0.006). Plasma fibulin-1 concentrations correlated with hemoglobin A1c (P < 0.001), arterial stiffness indices including pulse pressure (P < 0.001), and carotid compliance (P = 0.004), as well as plasma N-terminal pro–B-type natriuretic peptide concentrations (P < 0.001) and were predictive of 15-year mortality (P = 0.013). CONCLUSIONS Fibulin-1 accumulates in the arterial wall and in plasma of patients with type 2 diabetes, and appears to be a factor associated with arterial extracellular matrix changes in type 2 diabetes.
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CASTOLDI, Mirco, and Mon-Li CHU. "Structural and functional characterization of the human and mouse fibulin-1 gene promoters: role of Sp1 and Sp3." Biochemical Journal 362, no. 1 (February 8, 2002): 41–50. http://dx.doi.org/10.1042/bj3620041.
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Fibulin-1 is a multifunctional extracellular protein involved in diverse biological processes including cardiovascular development, haemostasis and cancer. To investigate the transcriptional regulation of the gene encoding fibulin-1 we cloned and analysed about 4.0kb of the 5′-flanking regions of both the human and mouse fibulin-1 genes. The human and mouse fibulin-1 promoters share little sequence similarity except for a short region of approx. 150–170bp immediately upstream of the translation start site. The conserved region contains a TATA-like sequence (ATAATT) and multiple consensus binding sites for Sp1 and activator protein 2 (AP-2). That the short conserved region in each gene confers basal promoter activity is demonstrated by transient transfections of promoter deletion constructs for both the human and mouse genes into cells that express fibulin-1 constitutively. Co-transfections of promoter constructs with expression plasmids for Sp1, Sp3 and Sp4 into Drosophila SL2 cells indicate that Sp1 and Sp3 are essential for transcriptional activation and that these two factors act synergistically. Electrophoretic mobility-shift assays show that Sp1 and Sp3, but not AP-2, bind to the basal promoter of the human fibulin-1 gene. The results demonstrate the functional importance of Sp1 and Sp3 in regulating the expression of the fibulin-1 gene.
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Zhang, Hong-Yan, Rupert Timpl, Takako Sasaki, Mon-Li Chu, and Peter Ekblom. "Fibulin-1 and fibulin-2 expression during organogenesis in the developing mouse embryo." Developmental Dynamics 205, no. 3 (March 1996): 348–64. http://dx.doi.org/10.1002/(sici)1097-0177(199603)205:3<348::aid-aja13>3.0.co;2-0.
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Zhang, Hangxiang, Jing Wu, Hailong Dong, Shaukat A. Khan, Mon-Li Chu, and Takeshi Tsuda. "Fibulin-2 deficiency attenuates angiotensin II-induced cardiac hypertrophy by reducing transforming growth factor-β signalling." Clinical Science 126, no. 4 (October 14, 2013): 275–88. http://dx.doi.org/10.1042/cs20120636.
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AngII (angiotensin II) is a potent neurohormone responsible for cardiac hypertrophy, in which TGF (transforming growth factor)-β serves as a principal downstream mediator. We recently found that ablation of fibulin-2 in mice attenuated TGF-β signalling, protected mice against progressive ventricular dysfunction, and significantly reduced the mortality after experimental MI (myocardial infarction). In the present study, we investigated the role of fibulin-2 in AngII-induced TGF-β signalling and subsequent cardiac hypertrophy. We performed chronic subcutaneous infusion of AngII in fibulin-2 null (Fbln2−/−), heterozygous (Fbln2+/−) and WT (wild-type) mice by a mini-osmotic pump. After 4 weeks of subpressor dosage of AngII infusion (0.2 μg/kg of body weight per min), WT mice developed significant hypertrophy, whereas the Fbln2−/− showed no response. In WT, AngII treatment significantly up-regulated mRNAs for fibulin-2, ANP (atrial natriuretic peptide), TGF-β1, Col I (collagen type I), Col III (collagen type III), MMP (matrix metalloproteinase)-2 and MMP-9, and increased the phosphorylation of TGF-β-downstream signalling markers, Smad2, TAK1 (TGF-β-activated kinase 1) and p38 MAPK (mitogen-activated protein kinase), which were all unchanged in AngII-treated Fbln2−/− mice. The Fbln2+/− mice consistently displayed AngII-induced effects intermediate between WT and Fbln2−/−. Pressor dosage of AngII (2 mg/kg of body weight per min) induced significant fibrosis in WT but not in Fbln2−/− mice with comparable hypertension and hypertrophy in both groups. Isolated CFs (cardiac fibroblasts) were treated with AngII, in which direct AngII effects and TGF-β-mediated autocrine effects was observed in WT. The latter effects were totally abolished in Fbln2−/− cells, suggesting that fibulin-2 is essential for AngII-induced TGF-β activation. In conclusion our data indicate that fibulin-2 is essential for AngII-induced TGF-β-mediated cardiac hypertrophy via enhanced TGF-β activation and suggest that fibulin-2 is a potential therapeutic target to inhibit AngII-induced cardiac remodelling.
Dissertations / Theses on the topic "Fibulin-2"
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Shuen, Wai-ho, and 孫偉豪. "Mechanistic studies of fibulin-2 and its related signaling pathways in nasopharyngeal carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206469.
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Nasopharyngeal carcinoma (NPC) has distinctive ethnic and geographic distributions, with the highest incidence in Southern China. Epstein-Barr virus (EBV) infection, non-viral environmental risk factors, and host genetics contribute to the development of NPC. In our previous studies, Fibulin-2 (FBLN2), located at chromosome 3p25.1, has been identified as a candidate tumor suppressor gene (TSG) in nasopharyngeal carcinoma (NPC) by using a chromosome 3 NotI genomic microarray screen, followed by functional assays. FBLN2 belongs to the fibulin family of extracellular matrix glycoproteins. It encodes a large protein consisting of cysteinerich and cysteine-free segments, three anaphylatoxin (AT) modules, a series of cbEGFlike repeated, and a fibulin module. Although FBLN2 was also identified as a candidate TSG in other cancers, its molecular characterization is still largely unknown.
In the present study, lentiviral constitutive and inducible transgene expression systems, fluorescent protein labelling and reporter systems, and shRNA-mediated knockdown system were optimized and established for studies in NPC. With the use of lentiviral systems, the FBLN2-mediated signaling pathways and the functions of FBLN2-related p65 signaling pathway were revealed. Lentiviral pWPI-FBLN2 infected HONE1, HK1, and C666 cell lines consistently reduced p65 phosphorylation at serine S536. Also, FBLN2 was shown to inactivate RhoA and Cdc42, resulting in decreased stress fiber and filopodia formation. Full-length and truncated FBLN2 fragments, with the exception of anaphylatoxin module, reduced phosphorylation of p65 as well as suppressed HUVEC tube formation. The p65 pathway was then chosen for in-depth studies. Inactivation of p65 by p65 stable knockdown and IκBα super repressor overexpression showed reduced cell migration, invasion, angiogenesis, in vitro cell growth, and in vivo tumor growth. In contrast, overexpression of wild type p65 and phospho-mimic S536E p65 promotes cell migration, invasion, angiogenesis, in vitro cell growth, and cell cycle progression. Molecular studies suggested that tumorassociated angiogenesis is regulated by p65 through expression of pro-angiogenic factors and the p65 activity controls epithelial-to-mesenchymal transition (EMT)-like properties in NPC. Western blotting and qPCR analyses showed that inactivation of p65 reduced expression of pro-angiogenic factors and mesenchymal markers. Overexpression of p65 induced expression of pro-angiogenic factors and mesenchymal markers as well as enhanced EMT-like properties. The elimination of the p65 feedback mechanism by IκBα knockdown largely induced expression of pro-angiogenic factors and mesenchymal markers, as well as changes in cell morphology.
In conclusion, these results suggest that FBLN2 suppresses tumor growth, tumor-associated angiogenesis, migration, and invasion through the regulation of Erk1/2, p65, and Rho GTPase pathways. The important roles of the p65 pathway in angiogenesis and EMT were also revealed. These findings provide a strategic new insight into the understanding of mechanistic role of FBLN2 in NPC and provide a better understanding for the molecular genetic basis of NPC tumorigenesis.published_or_final_version
Clinical Oncology
Doctoral
Doctor of Philosophy
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de, Bock Charles Edo St George Clinical School UNSW. "Novel protein interactors of urokinase-type plasminogen activator receptor." Awarded by:University of New South Wales. St George Clinical School, 2005. http://handle.unsw.edu.au/1959.4/23009.
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The plasminogen activator (PA) system plays an important role in cell adhesion, migration and invasion, and may require the coordinated expression of various proteins. The human urokinase-type plasminogen activator (uPA) receptor (uPAR) is a central protein component of the PA system. By binding its ligand uPA, uPAR can direct proteolysis of the extracellular matrix. Also, it is now apparent that uPAR can initiate proteolytic independent signal transduction to influence angiogenesis, inflammation, wound repair and tumour progression. To determine whether any novel proteins interacted with uPAR, a yeast two-hybrid screening analysis was undertaken using alternate uPAR domain constructs as baits. These included full-length three domain uPAR (uPAR-DIDIIDIII), two domain uPAR (uPAR-DIIDIII), and each individual uPAR domain (uPAR-DI, uPAR-DII and uPAR-DIII). A number of proteins were identified as putative candidate interactors for the alternate constructs, with two of special interest for uPAR-DIDIIDIII. These were the heat shock protein Mrj, and the extracellular matrix protein fibulin-2. The protein Mrj was shown to bind uPAR both in vitro and in vivo using GST-pull down and co-immunoprecipitation assays respectively. The GST-pull down assay identified the interaction between Mrj and uPAR dependent on the C-terminal domain of Mrj and DI of uPAR. Using in vivo co-immunoprecipitation analysis, Mrj also bound to uPAR. Preliminary data suggest the association between uPAR and Mrj may play a role in the regulation of apoptosis. In regard to the uPAR interactor of fibulin-2, a calcium dependent binding interaction with uPAR was identified using the GST-pull down assay. However due to the large molecular weight and stringent conditions needed to solubilise fibulin-2, it was not possible to co-immunoprecipitate both uPAR and fibulin-2. Together, the identification of both Mrj and fibulin-2 amongst other candidate interactors of uPAR presented here provides further insight into the intricate relationship between uPAR and other proteins which may influence a range of biological functions.
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Horiguchi, Masahito. "Latent TGF-β-binding protein 2 binds to DANCE/fibulin-5 and regulates elastic fiber assembly." Kyoto University, 2008. http://hdl.handle.net/2433/135796.
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Serra, Encinas Noemí. "Estudi genètic d’associació de fibulines i hipertensió arterial i regulació farmacològica de la seva expressió." Doctoral thesis, Universitat Rovira i Virgili, 2016. http://hdl.handle.net/10803/351954.
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La composició i l'estructura de la matriu extracel·lular a la paret vascular i a les plaques arterioscleròtiques, sòn factors molt importants que determinen la rigidesa vascular i l'estabilitat de la placa. D'altra banda, la rigidesa arterial és un factor clau per la hipertensió arterial. S'ha descrit que les fibulines -1,-2,-4 i -5 són proteïnes estructuradores de la matriu extracel·lular involucrades en diverses malalties cardiovasculars. Així doncs, hem dissenyat un estudi genetic per valorar l'associació de diversos SNPs de les fibulines -1, -2 i -5 amb la hipertensió arterial (HTA) i un estudi in vitro per avaluar els efectes de fàrmacs utilitzats en la prevenció cardiovascular sobre l’expressió gènica i proteica de les fibulines -1, -2, -4 i -5. Hem demostrat que variacions en el gen de la FBLN2 (rs3732666 i rs10061376) estan associats a menor presió arterial sistòlica i menor risc de patir HTA i que el rs3732666 també està associat en diferents graus amb un menor gruix de la íntima-mèdia carotídia. A més, en el segon estudi hem descrit que en cèl·lules musculars llises humanes, 24 h de tractament amb simvastatina augmenta l’expressió de fibulina-2 intracel·lular i secretada tant a nivell gènic com a nivell proteic. A més, hem demostrat que el mecanisme involucrat és la inhibició de la via RhoA/ROCK. Aquests resultats són la primera evidència de que el gen de la FBLN2 es troba associat a la HTA i que l’expressió de fibulina-2 està regulada per fàrmacs utilitzats com a teràpia preventiva cardiovascular. Així doncs, l’efecte de la simvastatina sobre l’expressió de fibulina-2 podria afegir-se a la llarga llista d'efectes pleiotròpics de les estatines.La composición y estructura de la matriz extracelular en la pared vascular i en las placas arterioscleróticas, son factores muy importantes que determinan la rigidez vascular i la estabilidad de la placa. Por otro lado, la rigidez arterial es un factor clave para la hipertensión arterial. Se ha descrito que las fibulinas -1,-2,-4 y -5 son proteínas estructurales de la matriz extracelular involucradas en diferentes enfermedades cardiovasculares. Por estos motivos, hemos diseñado un estudio genético para valorar la asociación de varios SNPs de las fibulinas -1,-2 y -5 con la hipertensión arterial(HTA) y un estudio in vitro para evaluar los efectos de fármacos utilizados en la prevención cardiovascular sobre la expresión génica y proteica de las fibulinas -1,-2,-4 y -5. Hemos demostrado que variaciones en el gen de la FBLN2(rs3732666 i rs10061376) están asociadas a menor presión arterial sistólica y menos riesgo de padecer HTA i que el rs3732666 también se asocia en diferentes niveles con un menor grosor de la íntima-media carotídeo. Además, en el segundo estudio hemos descrito que en células musculares lisas humanas, 24h de tratamiento con simvastatina aumenta la expresión de fibulina-2 intracelular y secretada tanto a nivel génico como proteico. Además hemos demostrado que el mecanismo involucrado es la inhibición de la via RhoA/ROCK. Estos resultados son la primera evidencia de que el gen de la FBLN2 se asocia con la HTA y que la expresión de fibulina-2 esta regulada por fármacos utilizados como terapia preventiva cardiovascular. De esta manera, el efecto de la simvastatina sobre la expresión de fibulina-2 se podría incluir a la larga lista de efectos pleiotrópicos de las estatinas.
The composition and structure of the extracellular matrix in the vascular wall and atherosclerotic plaque are important factors that determine vascular stiffnes and plaque stability . Furthermore, arterial stiffness is a key factor for hypertension. Described the fibulins -1,-2,-4 and-5 are structural proteins of the extracellular matrix involved in several cardiovascular diseases. So we designed a study to assess the genetic association of multiple SNPs of fibulins -1, -2 and -5 with high blood pressure and an in vitro study to evaluate the effects of drugs used in cardiovascular prevention on gene and protein expression of fibulins -1, -2 , -4. We have shown that variations in the gene FBLN2 ( rs3732666 and rs10061376 ) are associated with lower systolic blood pressure and lower risk of hypertension and also that rs3732666 is associated to varying degrees with a lower intima-media thickness of the carotid . In addition, in the second study described that simvastatin increases gene and protein expression of fibulin-2 at 24 hours of treatment in human smooth muscle cells. Also we demonstrated that the mechanism involved is via inhibition of RhoA / ROCK . These results are the first evidence that gene FBLN2 is associated with hypertension and fibulina -2 expression is regulated by drugs used as preventive cardiovascular. Thus, the effect of simvastatin on the expression of fibulina- 2 could be added to the long list of pleiotropic effects of statins .
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Pless, Elin. "Investigation of interactions with extracellular matrix proteins mediated by the CCP modules of the metabotropic GABAB receptor." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/5714.
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GABAB receptors are G-protein coupled receptors for the major inhibitory neurotransmitter in the mammalian central nervous system, γ-aminobutyric acid (GABA). The receptor is linked to a variety of disorders including epilepsy, pain, spasticity, drug addiction and cognitive impairment and is, therefore of major importance for drug discovery. The most abundant receptor isoforms GABABR1a and R1b differ by the presence in R1a of a pair of Nterminal extracellular complement control protein modules (CCP1 and CCP2) which - in other proteins - are generally involved in mediating specific protein-protein recognition. The CCP1 module contains disulphides but is natively disordered. In the current work, the yeast two-hybrid system was used to confirm an interaction of CCP1 of GABABR1a with the extracellular protein fibulin-2. Further work with the yeast twohybrid system extablished the novel interaction of the abundant extracellular matrix protein laminin, with GABABR1a CCP1, via its laminin globular (LG) domains. The laminin interaction was further characterised by surface plasmon resonance, demonstrating that several different domains are involved in the binding to the GABAB receptor CCPs. The primary binding site is located on laminin α5 LG4-5, but the E10 domains of the β1 chain and LG1-3 on α1 may also be involved. The pharmacological properties of the GABABR1a and R1b isoforms were studied by transient expression in Xenopus laevis oocytes. It was demonstrated that the agonist baclofen, as well as the antagonist CGP55845, appear to be more potent at GABABR1b compared to GABABR1a. Intriguingly, when recorded in the precence of laminin, GABABR1b/R2 expressing oocytes exhibited an increased baclofen-evoked response while the response in GABABR1a/R2 was completely abolished. In conclusion, the work demonstrates that laminin is a binding partner for GABABR1a CCPs. Such an interaction between the metabotropic GABA receptor and the extracellular matrix may lie behind the recently reported roles of GABA in neuronal migration and the laying down of neuronal circuitry during the development of parts of the central nervous system.
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Papon, Marie-Amélie. "Régulation des sous-types d’hétérodimères du récepteur GABAB dans la moelle épinière en conditions de douleurs neuropathiques : rôle des protéines partenaires." Thesis, Bordeaux 2, 2009. http://www.theses.fr/2009BOR21671/document.
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Dans le système nerveux central, le récepteur inhibiteur GABAB est un archétype des RCPGs hétérodimériques. Il est composé en effet de deux sous-unités, la sous-unité GABAB1 (B1a ou B1b) qui lie l’agoniste et la sous-unité GABAB2 couplée aux protéines G. L’activation de ce récepteur a un effet antinociceptif bien établi concernant les douleurs aiguës mais son effet reste cependant très limité en cas de douleurs neuropathiques. Notre hypothèse est que son activation et sa signalisation peuvent être altérées par des protéines partenaires, aboutissant à des processus de désinhibition dans la moelle épinière en conditions de neuropathie. Nos résultats mettent en évidence le rôle de deux protéines partenaires qui sont surexprimées en conditions douloureuses et qui diminuent l’activation du récepteur GABAB via deux mécanismes différents. D’un part, la protéine cytosolique 14-3-3? induit la dissociation de l’hétérodimère B1b/B2. Cette action a lieu principalement dans les compartiments post-synaptiques. D’autre part, la fibuline-2, protéine de la matrice extracellulaire diminue l’activation de l’hétérodimère B1a/B2. Il s’agit cette fois préférentiellement d’une action dans les compartiments pré-synaptiques. Des stratégies anti-sens (siRNA anti-14-3-3? ou anti-fibuline-2) ou des peptides de compétition sélectifs de l’interaction B1b/14-3-3? permettent de potentialiser les effets antinociceptifs d’un agoniste du récepteur sur un modèle animal de neuropathie. L’ensemble de ces résultats suggèrent que l’état d’oligomérisation des RCPGs peut être modulé in vivo par des protéines partenaires endogènes impliquées dans le développement ou le maintien d’états pathologiques de sensibilisation à la douleurIn the central nervous system, the inhibitory GABAB receptor is an obligate heterodimeric GPCR that requires the association between GABAB1 (B1a or B1b) and GABAB2 subunits. The heterodimeric GABAB receptor activation has a well-known antinociceptive action in acute pain but its effect appears limited in pathological states. Our hypothesis is that the GABAB activation and signaling could be altered by partner proteins, thus resulting in desinhibition processes in the spinal cord. In the present study, we investigated the role of two partner proteins overexpressed in neuropathic states which decrease GABAB activation through two different mechanisms. On the one hand, the cytosolic 14-3-3? protein induces the dissociation of the heterodimer B1b/B2. This effect occurs in post-synaptic compartments. On the other hand, fibulin-2, an extracellular matrix protein, which decreases the activation of the heterodimer B1a/B2 localized preferentially in presynaptic compartments. Anti-sens strategies (anti-14-3-3? or anti-fibulin-2 siRNA) or competing peptides specific of 14-3-3?/B1b interaction, potentiate the antinociceptive effects of GABAB agonist in an animal model of neuropathic pain. Taken together, our data suggest that GPCR oligomeric state can be modulated in vivo by endogenous partners proteins that are involved in the development and the maintenance of pain sensitization
Book chapters on the topic "Fibulin-2"
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Tsuda, Takeshi, and Mon-Li Chu. "Biological Role of Fibulin-2 in Cardiovascular Development." In Cardiovascular Development and Congenital Malformations, 20–23. Malden, Massachusetts, USA: Blackwell Publishing Ltd, 2007. http://dx.doi.org/10.1002/9780470988664.ch6.
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Ikelle, Larissa, Muna I. Naash, and Muayyad R. Al-Ubaidi. "Role of Fibulins 2 and 5 in Retinal Development and Maintenance." In Retinal Degenerative Diseases, 275–80. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-75402-4_33.
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Amano, Satoshi. "Fibulin-5 Deposition in Human Skin: Decrease with Aging and UVB Exposure and Increase in Solar Elastosis." In Textbook of Aging Skin, 1–9. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27814-3_32-2.
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Ayad, Shirley, Ray Boot-Handford, Martin J. Humphries, Karl E. Kadler, and Adrian Shuttleworth. "Fibulin-2." In The Extracellular Matrix FactsBook, 156–57. Elsevier, 1998. http://dx.doi.org/10.1016/b978-012068911-8.50135-4.
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Ayad, Shirley, Ray Boot-Handford, Martin J. Humphries, Karl E. Kadler, and Adrian Shuttleworth. "Fibulin-1 fibulin, BM-90." In The Extracellular Matrix FactsBook, 153–55. Elsevier, 1998. http://dx.doi.org/10.1016/b978-012068911-8.50134-2.
Full textConference papers on the topic "Fibulin-2"
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Speelman, L., E. Moltzer, K. van der Heiden, P. van Heijningen, A. F. W. van der Steen, J. Essers, F. Gijsen, and J. Wentzel. "Biomechanical Characteristics of Aortic Aneurysms Generated in Fibulin-4 Deficient Mice." In ASME 2012 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2012. http://dx.doi.org/10.1115/sbc2012-80590.
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Aortic aneurysms affect approximately 5% of the elderly population and aneurysm rupture is responsible for a significant number of deaths in the western world. Risk factors for aortic aneurysm include high cholesterol, high blood pressure, and smoking. Fibulin-4 is a glycoprotein, which is expressed in medial layers of blood vessels and a critical component for the structural integrity and elasticity of the aortic wall [1]. Mice with reduced levels of Fibulin-4 develop aortic abnormalities similar to Fibulin-4 patients, such as dilation of the ascending aorta. A 4-fold reduction of Fibulin-4 expression (fib-4R/R) causes a severe dilation, while a mice with a 2-fold reduction (fib-4+/R) show an onset of aneurysm formation, comparable with the development of an aneurysm in aging humans [2].
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Wan, William, Hiromi Yanagisawa, and Rudolph L. Gleason. "Biomechanical and Microstructural Properties of Fibulin-5 Null Mice." In ASME 2009 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2009. http://dx.doi.org/10.1115/sbc2009-206435.
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Fibulin-5 is an extracellular matrix (ECM) protein that interacts with integrins and plays a critical role in organizing elastic fibers. Gross observation and histological examination reveal that carotid arteries from fibulin-5 knockout (fib5-/-) mice have disrupted elastic lamellae and are more tortuous [1]. The properties of fibulin-5 null mice provide a unique platform for developing constituent based models for vascular mechanics. While numerous models for blood vessels exist, there is a need to relate measurable microstructural metrics of structurally-based constitutive relations. We performed mechanical tests on carotid arteries from wildtype (WT) and fib5-/-mice and imaged live vessels under multiple loading scenarios to quantify microstructure during deformation. We also fit experimental results to a constitutive relation based on Holzapfel’s model [2]. These results provide a basis for further model development.
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Le, Victoria, Hiromi Yanagisawa, and Jessica Wagenseil. "Characterization of Cardiac Function and Arterial Mechanics During Early Postnatal Development in Fibulin-5 Null Mice." In ASME 2013 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2013. http://dx.doi.org/10.1115/sbc2013-14282.
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Fibulin-5 is an extracellular matrix protein that interacts with other proteins during a complex process that results in elastic fiber formation from the elastin precursor, tropoelastin [1]. Elastic fibers are an important component of tissues requiring elasticity, including large arteries, lungs and skin. In mice lacking fibulin-5 ( Fbln5−/−), these tissues contain disorganized elastic fibers and exhibit decreased elasticity [2]. The phenotype of Fbln5−/− mice is similar to that of humans with cutis laxa, a connective tissue disorder characterized by loose skin and narrow arteries with reduced compliance.
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Espinosa, Gabriela, Lisa Bennett, William Gardner, and Jessica Wagenseil. "The Effects of Extracellular Matrix Protein Insufficiency and Treatment on the Stiffness of Arterial Smooth Muscle Cells." In ASME 2013 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2013. http://dx.doi.org/10.1115/sbc2013-14131.
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Increased arterial stiffness is directly correlated with hypertension and cardiovascular disease. Stiffness of the conducting arteries is largely determined by the extracellular matrix (ECM) proteins in the wall, such as collagen and elastin, produced by the smooth muscle cells (SMCs) found in the medial layer. Elastin is deposited as soluble tropoelastin and is later crosslinked into elastin fibers. Newborn mice lacking the elastin protein ( Eln−/−) have increased arterial wall stiffness and SMCs with altered proliferation, migration and morphology [1]. Vessel elasticity is also mediated by other ECM proteins, such as fibulin-4. Elastic tissue, such as lung, skin, and arteries, from fibulin-4 deficient ( Fbln4−/−) mice show no decrease in elastin content, but have reduced elasticity due to disrupted elastin fibers [2]. Arteries from both elastin and fibulin-4 deficient mice have been previously studied, but the mechanical properties of their SMCs have not been investigated. Recent experiments comparing arterial SMCs from old and young animals suggest that mechanical properties of the SMCs themselves may contribute to changes in wall stiffness [3]. Hence, we investigated the stiffness of isolated arterial SMCs from elastin and fibulin-4 deficient mice using atomic force microscopy (AFM). In addition, we studied the effects of two elastin treatments on the mechanical properties of SMCs from Eln+/+ and Eln−/− mice. Differences between the treatments may elucidate the importance of soluble versus crosslinked elastin on single cell stiffness.
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Shuen, Wai Ho, and Maria Li Lung. "Abstract 4309: Fibulin-2 suppresses tumor growth and angiogenesis through the inhibition of Erk1/2 and p65 pathways in nasopharyngeal carcinoma." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-4309.
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Wan, William, and Rudolph L. Gleason. "Collagen Fiber Angle Quantification of Carotid Arteries From Fibulin-5 Null Mice." In ASME 2011 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2011. http://dx.doi.org/10.1115/sbc2011-53685.
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Recent studies have revealed that carotid arteries from fibulin-5 (fbln5) null mice exhibit altered biomechanical and microstructural properties [1–2]. While the previous studies outline quantitative differences in mechanical properties of arteries from fbln5 null and wildtype mice, physical microstructural differences have yet to be quantified. Measurement of microstructural parameters will provide a crucial link between previously quantified mechanical properties and biological effects of knocking out the fbln5 gene. Characterizing microstructural properties will also provide experimental data to validate structurally-motivated constitutive relations and growth and remodeling models [3–4]. In this study, we quantified collagen fiber orientation in carotid arteries from fbln5 null and wildtype mice; collagen in mouse carotid arteries were imaged using multiphoton microscopy and analyzed using a fast Fourier transform algorithm.
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Moore, John J., Robert M. Moore, Deepak Kumar, Joseph M. Mansour, Brian M. Mercer, Elizabeth Yohannes, Jillian Novak, and Mark Chance. "Differential Expression of Fibulin Family Proteins in Mechanically Strong vs. Weak Fetal Membrane Fragments." In ASME 2007 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2007. http://dx.doi.org/10.1115/sbc2007-175332.
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Untimely rupture of the fetal membranes (FM), the amnion and choriodecidua, which normally surround and protect the fetus prior to delivery, is a major cause of preterm birth and results in significant infant mortality and morbidity. The physiological mechanism which normally leads the FM to weaken and fail prior to birth is not known. Conventional thinking that FM rupture is precipitated by the stress of uterine contractions during labor fails to explain the 10% of term deliveries and 40% of preterm deliveries in which FM rupture is the sentinel event, preceding any uterine contractions. Recent studies from several laboratories indicate that the FM undergo a genetically-programmed, biochemically-mediated, maturation process, near term, which is characterized by collagen remodeling and apoptosis. In human FM, in contrast to rat membranes, these changes are limited to the region of the FM overlying the cervix [1]. In a series of publications, our group has demonstrated that human FM have a zone of physical weakness (decreased force to rupture and work to rupture relative to the other areas of the same FM) overlying the cervical opening of the uterus. We further demonstrate that this same zone is characterized by specific markers of increased collagen remodeling and apoptosis [1–3]. These regional characteristics develop prior to the onset of contractions of labor and persist until delivery. Furthermore, the rupture tear line of the FM intersects this weak zone and thus the rupture process is hypothesized to initiate in this weak zone [3]. In order to investigate how differences in the biochemical composition of the extra-cellular matrix of the weak and the strong zones of FM reflect their different biomechanical properties, we utilized a proteomics approach to identify differences in the abundance of specific proteins in weak and strong FM fragments. Initial 2-DIGE screening resolved differences in Fibulin 5 protein expression. This prompted further analysis of additional members of the Fibulin protein family.
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Unteregger, Gerhard, Volker Jung, Carolin Hach, Joern Kamradt, Matthias Saar, and Michael Stoeckle. "Abstract 2351: Down-regulation of Fibulin-5 in invasive growing primary prostate cancer cells." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-2351.
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Hu, Bin, Paula A. Agudelo, Joshua C. Saldivar, Hosung Sim, Claire E. Dolan, Maria E. Mora, Gerard J. Nuovo, Susan E. Cole, and Mariano S. Viapiano. "Abstract 2353: Fibulin-3, an extracellular matrix protein, regulates Notch signaling and promotes brain tumor cell invasion and survival." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-2353.
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