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James Bristow - One of the best experts on this subject based on the ideXlab platform.
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Tenascin x collagen elastin and the ehlers danlos syndrome
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2005Co-Authors: James Bristow, William A Carey, David Egging, Joost SchalkwijkAbstract:Tenascin-X is an extracellular matrix protein initially identified because of its overlap with the human CYP21B gene. Because studies of gene and protein function of other Tenascins had been poorly predictive of essential functions in vivo, we used a genetic approach that critically relied on an understanding of the genomic locus to uncover an association between inactivating Tenascin-X mutations and novel recessive and dominant forms of Ehlers-Danlos syndrome. Tenascin-X provides the first example of a gene outside of the fibrillar collagens and their processing enzymes that causes Ehlers-Danlos syndrome. Tenascin-X null mice recapitulate the skin findings of the human disease, confirming a causative role for this gene in Ehlers-Danlos syndrome. Further evaluation of these mice showed that Tenascin-X is an important regulator of collagen deposition in vivo, suggesting a novel mechanism of disease in this form of Ehlers-Danlos syndrome. Further studies suggest that Tenascin-X may do this through both direct and indirect interactions with the collagen fibril. Recent studies show that TNX effects on matrix extend beyond the collagen to the elastogenic pathway and matrix remodeling enzymes. Tenascin-X serves as a compelling example of how human experiments of nature can guide us to an understanding of genes whose function may not be evident from their sequence or in vitro studies of their encoded proteins.
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a recessive form of the ehlers danlos syndrome caused by Tenascin x deficiency
The New England Journal of Medicine, 2001Co-Authors: Joost Schalkwijk, Walter L Miller, M C Zweers, Peter M Steijlen, Willow B Dean, Glen Taylor, Ivonne M Van Vlijmen, Brigitte Van Haren, James BristowAbstract:Background The Ehlers–Danlos syndrome is a heritable connective-tissue disorder caused by defects in fibrillar-collagen metabolism. Mutations in the type V collagen genes account for up to 50 percent of cases of classic Ehlers–Danlos syndrome, but many other cases are unexplained. We investigated whether the deficiency of the Tenascins, extracellular-matrix proteins that are highly expressed in connective tissues, was associated with the Ehlers–Danlos syndrome. Methods We screened serum samples from 151 patients with the classic, hypermobility, or vascular types of the Ehlers–Danlos syndrome; 75 patients with psoriasis; 93 patients with rheumatoid arthritis; and 21 healthy persons for the presence of Tenascin-X and Tenascin-C by enzyme-linked immunosorbent assay. We examined the expression of Tenascins and type V collagen in skin by immunohistochemical methods and sequenced the Tenascin-X gene. Results Tenascin-X was present in serum from all normal subjects, all patients with psoriasis, all patients with...
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Tenascin x deficiency is associated with ehlers danlos syndrome
Nature Genetics, 1997Co-Authors: Grant Burch, Yan Gong, Robert W Dettman, Cynthia J R Curry, Lynne T Smith, Walter L Miller, James BristowAbstract:The Tenascins are a family of large extracellular matrix proteins with at least three members: Tenascin-X (TNX)1–3, Tenascin-C (TNC, or cytotactin)4–6 and Tenascin-R (TN-R, or restrict in)7,8. Although the Tenascins have been implicated in a number of important cellular processes, no function has been clearly established for any Tenascin9. We describe a new contiguous-gene syndrome, involving the CYP21B and TNX genes, that results in 21-hydroxylase deficiency and a connective-tissue disorder consisting of skin and joint hyperextensibility, vascular fragility and poor wound healing. The connective tissue findings are typical of the Ehlers-Danlos syndrome (EDS)10. The abundant expression of TNX in connective tissues2,11–13 is consistent with a role in EDS, and our patient's skin fibroblasts do not synthesize TNX protein in vitro or in vivo. His paternal allele carries a novel deletion arising from recombination between TNX and its partial duplicate gene, XA14, which precludes TNX synthesis. Absence of TNX mRNA and protein in the proband, mapping of the TNX gene and HLA typing of this family suggest recessive inheritance of TNX deficiency and connective-tissue disease. Although the precise role of TNX in the pathogenesis of EDS is uncertain, this patient's findings suggest a unique and essential role for TNX in connective-tissue structure and function.
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Tenascin x a novel extracellular matrix protein encoded by the human xb gene overlapping p450c21b
Journal of Cell Biology, 1993Co-Authors: James Bristow, Stephen E Gitelman, Synthia H Mellon, Walter L MillerAbstract:A human gene termed XB overlaps the P450c21B gene encoding steroid 21-hydroxylase and encodes a protein that closely resembles extracellular matrix proteins. Sequencing of phage and cosmid clones and of cDNA fragments shows that the XB gene spans 65 kb of DNA, consisting of 39 exons that encode a 12-kb mRNA. The predicted protein of over 400 kD consists of five distinct domains: a signal peptide, a hydrophobic domain containing three heptad repeats, a series of 18.5 EGF-like repeats, 29 fibronectin type III repeats, and a carboxy-terminal fibrinogen-like domain. Because the structure of the protein encoded by the XB gene closely resembles Tenascin, we term this protein Tenascin-X (TN-X), and propose a simplified nomenclature system for the family of Tenascins. RNase protection experiments show that the TN-X transcript is expressed ubiquitously in human fetal tissues, with the greatest expression in the fetal testis and in fetal skeletal, cardiac, and smooth muscle. Two adrenal-specific transcripts, P450c21B (steroid 21-hydroxylase) and Y (an untranslated transcript) overlap the XB gene on the complementary strand of DNA, yielding a unique array of overlapping transcripts: a "polygene." In situ hybridization histochemistry experiments show that the TN-X transcript and the P450c21 and Y transcripts encoded on the complementary DNA strand are all expressed in the same cells of the human adrenal cortex. Genetic data suggest that TN-X may be essential for life.
Gertraud Orend - One of the best experts on this subject based on the ideXlab platform.
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Tenascin c at a glance
Journal of Cell Science, 2016Co-Authors: Kim S Midwood, Richard P Tucker, Matthias Chiquet, Gertraud OrendAbstract:ABSTRACT Tenascin-C (TNC) is a hexameric, multimodular extracellular matrix protein with several molecular forms that are created through alternative splicing and protein modifications. It is highly conserved amongst vertebrates, and molecular phylogeny indicates that it evolved before fibronectin. Tenascin-C has many extracellular binding partners, including matrix components, soluble factors and pathogens; it also influences cell phenotype directly through interactions with cell surface receptors. Tenascin-C protein synthesis is tightly regulated, with widespread protein distribution in embryonic tissues, but restricted distribution of Tenascin-C in adult tissues. Tenascin-C is also expressed de novo during wound healing or in pathological conditions, including chronic inflammation and cancer. First described as a modulator of cell adhesion, Tenascin-C also directs a plethora of cell signaling and gene expression programs by shaping mechanical and biochemical cues within the cellular microenvironment. Exploitment of the pathological expression and function of Tenascin-C is emerging as a promising strategy to develop new diagnostic, therapeutic and bioengineering tools. In this Cell Science at a Glance article and the accompanying poster we provide a succinct and comprehensive overview of the structural and functional features of Tenascin-C and its potential roles in developing embryos and under pathological conditions.
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The adhesion modulating properties of Tenascin-w
International Journal of Biological Sciences, 2011Co-Authors: Florence Brellier, Ruth Chiquet-ehrismann, Matthias Chiquet, Enrico Martina, Jacqueline Ferralli, Michael Van Der Heyden, Gertraud Orend, Johannes C. Schittny, Richard P TuckerAbstract:Tenascins are extracellular matrix glycoproteins associated with cell motility, proliferation and differentiation. Tenascin-C inhibits cell spreading by binding to fibronectin; Tenascin-R and Tenascin-X also have anti-adhesive properties in vitro. Here we have studied the adhesion modulating properties of the most recently characterized Tenascin, Tenascin-W. C2C12 cells, a murine myoblast cell line, will form broad lamellipodia with stress fibers and focal adhesion complexes after culture on fibronectin. In contrast, C2C12 cells cultured on Tenascin-W fail to spread and form stress fibers or focal adhesion complexes, and instead acquire a multipolar shape with short, actin-tipped pseudopodia. The same stellate morphology is observed when C2C12 cells are cultured on a mixture of fibronectin and Tenascin-W, or on fibronectin in the presence of soluble Tenascin-W. Tenascin-W combined with fibronectin also inhibits the spreading of mouse embryo fibroblasts when compared with cells cultured on fibronectin alone. The similarity between the adhesion modulating effects of Tenascin-W and Tenascin-C in vitro led us to study the possibility of Tenascin-W compensating for Tenascin-C in Tenascin-C knockout mice, especially during epidermal wound healing. Dermal fibroblasts harvested from a Tenascin-C knockout mouse express Tenascin-W, but dermal fibroblasts taken from a wild type mouse do not. However, there is no upregulation of Tenascin-W in the dermis of Tenascin-C knockout mice, or in the granulation tissue of skin wounds in Tenascin-C knockout animals. Similarly, Tenascin-X is not upregulated in early wound granulation tissue in the Tenascin-C knockout mice. Thus, Tenascin-W is able to inhibit cell spreading in vitro and it is upregulated in dermal fibroblasts taken from the Tenascin-C knockout mouse, but neither it nor Tenascin-X are likely to compensate for missing Tenascin-C during wound healing.
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advances in Tenascin c biology
Cellular and Molecular Life Sciences, 2011Co-Authors: Kim S Midwood, Benoit Langlois, Thomas Hussenet, Gertraud OrendAbstract:Tenascin-C is an extracellular matrix glycoprotein that is specifically and transiently expressed upon tissue injury. Upon tissue damage, Tenascin-C plays a multitude of different roles that mediate both inflammatory and fibrotic processes to enable effective tissue repair. In the last decade, emerging evidence has demonstrated a vital role for Tenascin-C in cardiac and arterial injury, tumor angiogenesis and metastasis, as well as in modulating stem cell behavior. Here we highlight the molecular mechanisms by which Tenascin-C mediates these effects and discuss the implications of mis-regulated Tenascin-C expression in driving disease pathology.
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the role of Tenascin c in tissue injury and tumorigenesis
Journal of Cell Communication and Signaling, 2009Co-Authors: Kim S Midwood, Gertraud OrendAbstract:The extracellular matrix molecule Tenascin-C is highly expressed during embryonic development, tissue repair and in pathological situations such as chronic inflammation and cancer. Tenascin-C interacts with several other extracellular matrix molecules and cell-surface receptors, thus affecting tissue architecture, tissue resilience and cell responses. Tenascin-C modulates cell migration, proliferation and cellular signaling through induction of pro-inflammatory cytokines and oncogenic signaling molecules amongst other mechanisms. Given the causal role of inflammation in cancer progression, common mechanisms might be controlled by Tenascin-C during both events. Drugs targeting the expression or function of Tenascin-C or the Tenascin-C protein itself are currently being developed and some drugs have already reached advanced clinical trials. This generates hope that increased knowledge about Tenascin-C will further improve management of diseases with high Tenascin-C expression such as chronic inflammation, heart failure, artheriosclerosis and cancer.
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Tenascin w is a novel marker for activated tumor stroma in low grade human breast cancer and influences cell behavior
Cancer Research, 2007Co-Authors: Martin Degen, Florence Brellier, Luigi Terracciano, Christian Ruiz, Gertraud Orend, Renate Kain, Ruth ChiquetehrismannAbstract:This is the first report about human Tenascin-W, the fourth and final member of the extracellular matrix protein family of Tenascins. Sixty-three human breast tumor extracts were analyzed by Western blotting for the presence of Tenascin-W and compared with Tenascin-C, an established marker of tumor stroma. Interestingly, we found Tenascin-W expression in the majority of the tumor tissues, but no detectable expression in the normal mammary parenchyma. Eighty-one percent of the breast tumor samples were Tenascin-W positive and 86% showed expression of Tenascin-C. However, Tenascin-W and Tenascin-C amounts varied greatly between tumors and some contained either Tenascin-W or Tenascin-C exclusively, indicating independent mechanisms regulating their expression. Although there was no difference between high- or low-grade tumors with respect to the presence of Tenascin-C, Tenascin-W was more prominent in low-grade tumors. For 42 of the breast cancer tissues, a frozen tumor microarray was available to confirm the Western blot data by immunohistochemistry. Similar to Tenascin-C, Tenascin-W was detected in the tumor stroma. Fibroblasts adhered to Tenascin-W in a β1 integrin–dependent manner and spread with a distinctive morphology under conditions where they remained round on Tenascin-C. CHOB2 cells expressing αvβ1 or α4β1 integrins were able to spread on Tenascin-W. Furthermore, addition of Tenascin-W to the culture medium increased migration of breast cancer cells toward a fibronectin substratum in vitro . These data imply that Tenascin-W expression in the activated tumor stroma facilitates tumorigenesis by supporting the migratory behavior of breast cancer cells. [Cancer Res 2007;67(19):9169–79]
Joost Schalkwijk - One of the best experts on this subject based on the ideXlab platform.
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Abdominal aortic aneurysm is associated with high serum levels of Tenascin-X and decreased aneurysmal tissue Tenascin-X.
Circulation, 2006Co-Authors: Manon C. Zweers, Anita C.t.m. Peeters, Sietze Graafsma, Steef Kranendonk, J. Adam Van Der Vliet, Martin Den Heijer, Joost SchalkwijkAbstract:Background— Tenascin-X is a large extracellular matrix protein that is abundantly expressed in several connective tissues. A 140-kDa C-terminal fragment of Tenascin-X is present in human serum. Complete deficiency of Tenascin-X is associated with Ehlers-Danlos syndrome, and these patients show major connective tissue alterations in their skin, as well as blood vessel fragility. In this study, we investigated whether Tenascin-X is present in normal human aorta and abdominal aortic aneurysm (AAA) tissues and whether an association exists between serum Tenascin-X levels and AAA. Methods and Results— Five normal aortas and 5 AAA tissues were immunostained for Tenascin-X and elastin. Tenascin-X was present throughout the entire aorta and was especially abundant near the elastic lamellae, whereas Tenascin-X expression was strongly decreased in AAA tissue. Measurement of Tenascin-X serum concentration by enzyme-linked immunosorbent assay (ELISA) in 87 AAA patients and 86 controls demonstrated an increasing risk ...
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Tenascin x collagen elastin and the ehlers danlos syndrome
American Journal of Medical Genetics Part C-seminars in Medical Genetics, 2005Co-Authors: James Bristow, William A Carey, David Egging, Joost SchalkwijkAbstract:Tenascin-X is an extracellular matrix protein initially identified because of its overlap with the human CYP21B gene. Because studies of gene and protein function of other Tenascins had been poorly predictive of essential functions in vivo, we used a genetic approach that critically relied on an understanding of the genomic locus to uncover an association between inactivating Tenascin-X mutations and novel recessive and dominant forms of Ehlers-Danlos syndrome. Tenascin-X provides the first example of a gene outside of the fibrillar collagens and their processing enzymes that causes Ehlers-Danlos syndrome. Tenascin-X null mice recapitulate the skin findings of the human disease, confirming a causative role for this gene in Ehlers-Danlos syndrome. Further evaluation of these mice showed that Tenascin-X is an important regulator of collagen deposition in vivo, suggesting a novel mechanism of disease in this form of Ehlers-Danlos syndrome. Further studies suggest that Tenascin-X may do this through both direct and indirect interactions with the collagen fibril. Recent studies show that TNX effects on matrix extend beyond the collagen to the elastogenic pathway and matrix remodeling enzymes. Tenascin-X serves as a compelling example of how human experiments of nature can guide us to an understanding of genes whose function may not be evident from their sequence or in vitro studies of their encoded proteins.
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Transplantation of reconstructed human skin on nude mice: a model system to study expression of human Tenascin-X and elastic fiber components
Cell and Tissue Research, 2005Co-Authors: Manon C. Zweers, Joost Schalkwijk, Toin H. Kuppevelt, Ivonne M. Vlijmen-willems, Mieke Bergers, Claire Lethias, Evert N. LammeAbstract:Tenascin-X is a large extracellular matrix protein that is widely expressed in connective tissues during development and in the adult. Genetically determined deficiency of Tenascin-X causes the connective tissue disease Ehlers–Danlos syndrome. These patients show reduced collagen density and fragmentation of elastic fibers in their skin. In vitro studies on the role of Tenascin-X in elastic fiber biology are hampered because monolayers of fibroblasts do not deposit Tenascin-X and elastic fibers into the extracellular matrix. Here, we applied an organotypic culture model of fibroblasts and keratinocytes to address this issue. We investigated the deposition of Tenascin-X and elastin into skin-equivalent in vitro and also in vivo after transplantation onto immunodeficient mice. Whereas Tenascin-C and fibrillin-1 were readily expressed in the skin-equivalents before transplantation, Tenascin-X and elastin were not present. Three weeks post-grafting, a network of elastin was observed that coincided with the appearance of Tenascin-X. At the ultrastructural level, microfibrils were observed, some of which were associated with elastin. Transplanted skin-equivalents containing Tenascin-X-deficient fibroblasts showed deposition of immunoreactive elastin in similar quantities and distribution as those containing control fibroblasts. This suggests that Tenascin-X is important for the stability and maintenance of established elastin fibers, rather than for the initial phase of elastogenesis. Thus, the transplantation of reconstructed skin on nude mice allows the study of Tenascin-X and elastin expression and could be used as a model system to study the potential role of Tenascin-X in matrix assembly and stability.
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a recessive form of the ehlers danlos syndrome caused by Tenascin x deficiency
The New England Journal of Medicine, 2001Co-Authors: Joost Schalkwijk, Walter L Miller, M C Zweers, Peter M Steijlen, Willow B Dean, Glen Taylor, Ivonne M Van Vlijmen, Brigitte Van Haren, James BristowAbstract:Background The Ehlers–Danlos syndrome is a heritable connective-tissue disorder caused by defects in fibrillar-collagen metabolism. Mutations in the type V collagen genes account for up to 50 percent of cases of classic Ehlers–Danlos syndrome, but many other cases are unexplained. We investigated whether the deficiency of the Tenascins, extracellular-matrix proteins that are highly expressed in connective tissues, was associated with the Ehlers–Danlos syndrome. Methods We screened serum samples from 151 patients with the classic, hypermobility, or vascular types of the Ehlers–Danlos syndrome; 75 patients with psoriasis; 93 patients with rheumatoid arthritis; and 21 healthy persons for the presence of Tenascin-X and Tenascin-C by enzyme-linked immunosorbent assay. We examined the expression of Tenascins and type V collagen in skin by immunohistochemical methods and sequenced the Tenascin-X gene. Results Tenascin-X was present in serum from all normal subjects, all patients with psoriasis, all patients with...
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Tenascin expression in hyperproliferative skin diseases
British Journal of Dermatology, 1991Co-Authors: Joost Schalkwijk, I. M. J. J. Van Vlijmen, B. Oosterling, C. M. Perret, R. Koopman, J. Van Den Born, Eleanor J. MackieAbstract:Summary The expression of Tenascin, a recently discovered extracellular matrix glycoprotein, was studied by immunohistochemistry in normal human skin and in a number of skin diseases with epidermal hyperproliferation such as psoriasis, basal cell carcinoma. Bowen's disease and solar keratosis. Tenascin expression in the upper dermis of normal skin was found to vary from almost absent to patchy along the basal membrane. Staining was continuous and intense around blood vessels, hair follicles and eccrine sweat ducts. In basal cell carcinoma a marked expression of Tenascin was found in the tumour stroma, especially adjacent to the basal membrane surrounding the tumour cell nests. In Bowen's disease and solar keratosis, Tenascin expression was found in the dermis next to the keratinocytes. In psoriasis the dermal papillae of clinically involved skin were intensely stained and a continuous band of Tenascin was present in the upper dermis along the basal membrane. The distribution of Tenascin differed from other known extracellular matrix components.
Ruth Chiquetehrismann - One of the best experts on this subject based on the ideXlab platform.
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the regulation of Tenascin expression by tissue microenvironments
Biochimica et Biophysica Acta, 2009Co-Authors: Richard P Tucker, Ruth ChiquetehrismannAbstract:Abstract Tenascins are a family of four extracellular matrix proteins: Tenascin-C, X, R and W. The four members of the family have strikingly diverse patterns of expression during development and in the adult organism indicating independent mechanisms of regulation. In this review we illustrate that there are two types of Tenascins, those that are significantly regulated by the tissue microenvironment (Tenascin-C and Tenascin-W), and those that have stabile, restricted expression patterns (Tenascin-R and Tenascin-X). We summarize what is known about the regulation of Tenascin expression by transforming growth factor betas, fibroblast growth factors, platelet derived growth factors, as well as pro- and anti-inflammatory cytokines or hormones that either induce or inhibit expression of Tenascins.
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Tenascin w a new marker of cancer stroma is elevated in sera of colon and breast cancer patients
International Journal of Cancer, 2008Co-Authors: Martin Degen, Ruth Chiquetehrismann, Florence Brellier, Luigi Terracciano, Susanne Schenk, Robert Driscoll, K Zaman, Roger Stupp, Luigi Tornillo, Curzio RueggAbstract:Tenascins are extracellular matrix proteins present during the development of organisms as well as in pathological conditions. Tenascin-W, the fourth and last member of the Tenascin family remains the least well-characterized one. Our study aimed to evaluate the potential significance of Tenascin-W as cancer biomarker by monitoring its presence in the serum of colorectal and breast cancer patients and its expression in colorectal tumor tissues. To measure serum Tenascin-W levels, a sensitive sandwich-ELISA was established. Mean Tenascin-W concentration in sera of patients with nonmetastatic colorectal cancer at time of diagnosis was highly increased compared to that of healthy volunteers. A similar tendency was observed for Tenascin-C in the same patient cohort. However, the increase was much more striking for Tenascin-W. We also detected elevated Tenascin-W levels in sera of breast cancer patients. Furthermore, we could show a prominent expression of Tenascin-W in extracts from colorectal tumor tissues by immunoblot analysis, whereas Tenascin-W was not detectable in the corresponding normal colon mucosa. To confirm the western blot results, we performed immunohistochemistry of frozen sections of the same patients as well as of an additional, independently chosen collection of colorectal cancer tissues. In all cases, similarly to Tenascin-C, Tenascin-W was detected in the tumor stroma. Our results reveal a clear association between elevated levels of Tenascin-W and the presence of cancer. These results warrant further studies to evaluate the potential value of serum and tissue Tenascin-W levels as diagnostic, prognostic or monitoring biomarker in colorectal, breast and possibly other solid cancers.
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Tenascin w is a novel marker for activated tumor stroma in low grade human breast cancer and influences cell behavior
Cancer Research, 2007Co-Authors: Martin Degen, Florence Brellier, Luigi Terracciano, Christian Ruiz, Gertraud Orend, Renate Kain, Ruth ChiquetehrismannAbstract:This is the first report about human Tenascin-W, the fourth and final member of the extracellular matrix protein family of Tenascins. Sixty-three human breast tumor extracts were analyzed by Western blotting for the presence of Tenascin-W and compared with Tenascin-C, an established marker of tumor stroma. Interestingly, we found Tenascin-W expression in the majority of the tumor tissues, but no detectable expression in the normal mammary parenchyma. Eighty-one percent of the breast tumor samples were Tenascin-W positive and 86% showed expression of Tenascin-C. However, Tenascin-W and Tenascin-C amounts varied greatly between tumors and some contained either Tenascin-W or Tenascin-C exclusively, indicating independent mechanisms regulating their expression. Although there was no difference between high- or low-grade tumors with respect to the presence of Tenascin-C, Tenascin-W was more prominent in low-grade tumors. For 42 of the breast cancer tissues, a frozen tumor microarray was available to confirm the Western blot data by immunohistochemistry. Similar to Tenascin-C, Tenascin-W was detected in the tumor stroma. Fibroblasts adhered to Tenascin-W in a β1 integrin–dependent manner and spread with a distinctive morphology under conditions where they remained round on Tenascin-C. CHOB2 cells expressing αvβ1 or α4β1 integrins were able to spread on Tenascin-W. Furthermore, addition of Tenascin-W to the culture medium increased migration of breast cancer cells toward a fibronectin substratum in vitro . These data imply that Tenascin-W expression in the activated tumor stroma facilitates tumorigenesis by supporting the migratory behavior of breast cancer cells. [Cancer Res 2007;67(19):9169–79]
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Tenascin c induced signaling in cancer
Cancer Letters, 2006Co-Authors: Gertraud Orend, Ruth ChiquetehrismannAbstract:Tenascin-C is an adhesion modulatory extracellular matrix molecule that is highly expressed in the microenvironment of most solid tumors. High Tenascin-C expression reduces the prognosis of disease-free survival in patients with some cancers. The possible role of Tenascin-C in tumor initiation and progression is addressed with emphasis on underlying signaling mechanisms. How Tenascin-C affects malignant transformation, uncontrolled proliferation, angiogenesis, metastasis and escape from tumor immunosurveillance is summarized. Finally, we discuss how the phenotypes of Tenascin-C knock-out mice may help define the roles of Tenascin-C in tumorigenesis and how this knowledge could be applied to cancer therapy.
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interference of Tenascin c with syndecan 4 binding to fibronectin blocks cell adhesion and stimulates tumor cell proliferation
Cancer Research, 2001Co-Authors: Wentao Huang, Ruth Chiquetehrismann, Jose V Moyano, Angeles Garciapardo, Gertraud OrendAbstract:Tenascin-C is an adhesion-modulatory extracellular matrix molecule that is highly expressed in tumors. To investigate the effect of Tenascin-C on tumor cells, we analyzed its antiadhesive nature and effect on tumor cell proliferation in a fibronectin context. Glioblastoma and breast carcinoma cell adhesion was compromised by a mixed fibronectin/Tenascin-C substratum, which concomitantly caused increased tumor-cell proliferation. We identified the antiadhesive mechanism as a specific interference of Tenascin-C with cell binding to the HepII/syndecan-4 site in fibronectin through direct binding of Tenascin-C to the 13th fibronectin type III repeat (FNIII13). Cell adhesion and proliferation levels were restored by the addition of FNIII13. Overexpression of syndecan-4, but not syndecan-1 or -2, reverted the cell adhesion defect of Tenascin-C. We characterized FNIII13 as the binding site for syndecan-4. Thus we describe a novel mechanism by which Tenascin-C impairs the adhesive function of fibronectin through binding to FNIII13, thereby inhibiting the coreceptor function of syndecan-4 in fibronectin-induced integrin signaling.
Richard P Tucker - One of the best experts on this subject based on the ideXlab platform.
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Tenascin c at a glance
Journal of Cell Science, 2016Co-Authors: Kim S Midwood, Richard P Tucker, Matthias Chiquet, Gertraud OrendAbstract:ABSTRACT Tenascin-C (TNC) is a hexameric, multimodular extracellular matrix protein with several molecular forms that are created through alternative splicing and protein modifications. It is highly conserved amongst vertebrates, and molecular phylogeny indicates that it evolved before fibronectin. Tenascin-C has many extracellular binding partners, including matrix components, soluble factors and pathogens; it also influences cell phenotype directly through interactions with cell surface receptors. Tenascin-C protein synthesis is tightly regulated, with widespread protein distribution in embryonic tissues, but restricted distribution of Tenascin-C in adult tissues. Tenascin-C is also expressed de novo during wound healing or in pathological conditions, including chronic inflammation and cancer. First described as a modulator of cell adhesion, Tenascin-C also directs a plethora of cell signaling and gene expression programs by shaping mechanical and biochemical cues within the cellular microenvironment. Exploitment of the pathological expression and function of Tenascin-C is emerging as a promising strategy to develop new diagnostic, therapeutic and bioengineering tools. In this Cell Science at a Glance article and the accompanying poster we provide a succinct and comprehensive overview of the structural and functional features of Tenascin-C and its potential roles in developing embryos and under pathological conditions.
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The evolution of Tenascins and fibronectin
Cell Adhesion & Migration, 2015Co-Authors: Josephine C. Adams, Ruth Chiquet-ehrismann, Richard P TuckerAbstract:Tenascins are extracellular matrix glycoproteins that act both as integrin ligands and as modifiers of fibronectin-integrin interactions to regulate cell adhesion, migration, proliferation and differentiation. In tetrapods, both Tenascins and fibronectin bind to integrins via RGD and LDV-type tripeptide motifs found in exposed loops in their fibronectin-type III domains. We previously showed that Tenascins appeared early in the chordate lineage and are represented by single genes in extant cephalochordates and tunicates. Here we have examined the genomes of the coelacanth Latimeria chalumnae, the elephant shark Callorhinchus milii as well as the lampreys Petromyzon marinus and Lethenteron japonicum to learn more about the evolution of the Tenascin gene family as well as the timing of the appearance of fibronectin during chordate evolution. The coelacanth has 4 Tenascins that are more similar to tetrapod Tenascins than are Tenascins from ray-finned fishes. In contrast, only 2 Tenascins were identified in t...
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The adhesion modulating properties of Tenascin-w
International Journal of Biological Sciences, 2011Co-Authors: Florence Brellier, Ruth Chiquet-ehrismann, Matthias Chiquet, Enrico Martina, Jacqueline Ferralli, Michael Van Der Heyden, Gertraud Orend, Johannes C. Schittny, Richard P TuckerAbstract:Tenascins are extracellular matrix glycoproteins associated with cell motility, proliferation and differentiation. Tenascin-C inhibits cell spreading by binding to fibronectin; Tenascin-R and Tenascin-X also have anti-adhesive properties in vitro. Here we have studied the adhesion modulating properties of the most recently characterized Tenascin, Tenascin-W. C2C12 cells, a murine myoblast cell line, will form broad lamellipodia with stress fibers and focal adhesion complexes after culture on fibronectin. In contrast, C2C12 cells cultured on Tenascin-W fail to spread and form stress fibers or focal adhesion complexes, and instead acquire a multipolar shape with short, actin-tipped pseudopodia. The same stellate morphology is observed when C2C12 cells are cultured on a mixture of fibronectin and Tenascin-W, or on fibronectin in the presence of soluble Tenascin-W. Tenascin-W combined with fibronectin also inhibits the spreading of mouse embryo fibroblasts when compared with cells cultured on fibronectin alone. The similarity between the adhesion modulating effects of Tenascin-W and Tenascin-C in vitro led us to study the possibility of Tenascin-W compensating for Tenascin-C in Tenascin-C knockout mice, especially during epidermal wound healing. Dermal fibroblasts harvested from a Tenascin-C knockout mouse express Tenascin-W, but dermal fibroblasts taken from a wild type mouse do not. However, there is no upregulation of Tenascin-W in the dermis of Tenascin-C knockout mice, or in the granulation tissue of skin wounds in Tenascin-C knockout animals. Similarly, Tenascin-X is not upregulated in early wound granulation tissue in the Tenascin-C knockout mice. Thus, Tenascin-W is able to inhibit cell spreading in vitro and it is upregulated in dermal fibroblasts taken from the Tenascin-C knockout mouse, but neither it nor Tenascin-X are likely to compensate for missing Tenascin-C during wound healing.
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Tenascins and the Importance of Adhesion Modulation
Cold Spring Harbor Perspectives in Biology, 2011Co-Authors: Ruth Chiquet-ehrismann, Richard P TuckerAbstract:Tenascins are a family of extracellular matrix proteins that evolved in early chordates. There are four family members: Tenascin-X, Tenascin-R, Tenascin-W, and Tenascin-C. Tenascin-X associates with type I collagen, and its absence can cause Ehlers-Danlos Syndrome. In contrast, Tenascin-R is concentrated in perineuronal nets. The expression of Tenascin-C and Tenascin-W is developmentally regulated, and both are expressed during disease (e.g., both are associated with cancer stroma and tumor blood vessels). In addition, Tenascin-C is highly induced by infections and inflammation. Accordingly, the Tenascin-C knockout mouse has a reduced inflammatory response. All Tenascins have the potential to modify cell adhesion either directly or through interaction with fibronectin, and cell-Tenascin interactions typically lead to increased cell motility. In the case of Tenascin-C, there is a correlation between elevated expression and increased metastasis in several types of tumors.
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the regulation of Tenascin expression by tissue microenvironments
Biochimica et Biophysica Acta, 2009Co-Authors: Richard P Tucker, Ruth ChiquetehrismannAbstract:Abstract Tenascins are a family of four extracellular matrix proteins: Tenascin-C, X, R and W. The four members of the family have strikingly diverse patterns of expression during development and in the adult organism indicating independent mechanisms of regulation. In this review we illustrate that there are two types of Tenascins, those that are significantly regulated by the tissue microenvironment (Tenascin-C and Tenascin-W), and those that have stabile, restricted expression patterns (Tenascin-R and Tenascin-X). We summarize what is known about the regulation of Tenascin expression by transforming growth factor betas, fibroblast growth factors, platelet derived growth factors, as well as pro- and anti-inflammatory cytokines or hormones that either induce or inhibit expression of Tenascins.
