We are proudly a Ukrainian website. Our country was attacked by Russian Armed Forces on Feb. 24, 2022.
You can support the Ukrainian Army by following the link: https://u24.gov.ua/.
Even the smallest donation is hugely appreciated!
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the lists of relevant articles, books, theses, conference reports, and other scholarly sources on the topic 'Utrophin.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Marshall, Jamie L., Johan Holmberg, Eric Chou, Amber C. Ocampo, Jennifer Oh, Joy Lee, Angela K. Peter, Paul T. Martin, and Rachelle H. Crosbie-Watson. "Sarcospan-dependent Akt activation is required for utrophin expression and muscle regeneration." Journal of Cell Biology 197, no. 7 (June 25, 2012): 1009–27. http://dx.doi.org/10.1083/jcb.201110032.
Utrophin is normally confined to the neuromuscular junction (NMJ) in adult muscle and partially compensates for the loss of dystrophin in mdx mice. We show that Akt signaling and utrophin levels were diminished in sarcospan (SSPN)-deficient muscle. By creating several transgenic and knockout mice, we demonstrate that SSPN regulates Akt signaling to control utrophin expression. SSPN determined α-dystroglycan (α-DG) glycosylation by affecting levels of the NMJ-specific glycosyltransferase Galgt2. After cardiotoxin (CTX) injury, regenerating myofibers express utrophin and Galgt2-modified α-DG around the sarcolemma. SSPN-null mice displayed delayed differentiation after CTX injury caused by loss of utrophin and Akt signaling. Treatment of SSPN-null mice with viral Akt increased utrophin and restored muscle repair after injury, revealing an important role for the SSPN-Akt-utrophin signaling axis in regeneration. SSPN improved cell surface expression of utrophin by increasing transportation of utrophin and DG from endoplasmic reticulum/Golgi membranes. Our experiments reveal functions of utrophin in regeneration and new pathways that regulate utrophin expression at the cell surface.
2
Perkins, Kelly J., Utpal Basu, Murat T. Budak, Caroline Ketterer, Santhosh M. Baby, Olga Lozynska, John A. Lunde, Bernard J. Jasmin, Neal A. Rubinstein, and Tejvir S. Khurana. "Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle." Molecular Biology of the Cell 18, no. 8 (August 2007): 2864–72. http://dx.doi.org/10.1091/mbc.e06-12-1069.
Utrophin is the autosomal homologue of dystrophin, the protein product of the Duchenne's muscular dystrophy (DMD) locus. Utrophin expression is temporally and spatially regulated being developmentally down-regulated perinatally and enriched at neuromuscular junctions (NMJs) in adult muscle. Synaptic localization of utrophin occurs in part by heregulin-mediated extracellular signal-regulated kinase (ERK)-phosphorylation, leading to binding of GABPα/β to the N-box/EBS and activation of the major utrophin promoter-A expressed in myofibers. However, molecular mechanisms contributing to concurrent extrasynaptic silencing that must occur to achieve NMJ localization are unknown. We demonstrate that the Ets-2 repressor factor (ERF) represses extrasynaptic utrophin-A in muscle. Gel shift and chromatin immunoprecipitation studies demonstrated physical association of ERF with the utrophin-A promoter N-box/EBS site. ERF overexpression repressed utrophin-A promoter activity; conversely, small interfering RNA-mediated ERF knockdown enhanced promoter activity as well as endogenous utrophin mRNA levels in cultured muscle cells in vitro. Laser-capture microscopy of tibialis anterior NMJ and extrasynaptic transcriptomes and gene transfer studies provide spatial and direct evidence, respectively, for ERF-mediated utrophin repression in vivo. Together, these studies suggest “repressing repressors” as a potential strategy for achieving utrophin up-regulation in DMD, and they provide a model for utrophin-A regulation in muscle.
3
Moorwood, Catherine, Neha Soni, Gopal Patel, Steve D. Wilton, and Tejvir S. Khurana. "A Cell-Based High-Throughput Screening Assay for Posttranscriptional Utrophin Upregulation." Journal of Biomolecular Screening 18, no. 4 (October 30, 2012): 400–406. http://dx.doi.org/10.1177/1087057112465648.
Duchenne muscular dystrophy (DMD) is a devastating muscle-wasting disease caused by mutations in the dystrophin gene. Utrophin is a homologue of dystrophin that can compensate for its absence when overexpressed in DMD animal models. Utrophin upregulation is therefore a promising therapeutic approach for DMD. Utrophin is regulated at both transcriptional and posttranscriptional levels. Transcriptional regulation has been studied extensively, and assays have been described for the identification of utrophin promoter-targeting molecules. However, despite the profound impact that posttranscriptional regulation has on utrophin expression, screening assays have not yet been described that could be used to discover pharmaceuticals targeting this key phase of regulation. We describe the development and validation of a muscle cell line–based assay in which a stably expressed luciferase coding sequence is flanked by the utrophin 5′- and 3′-untranslated regions (UTRs). The assay was validated using the posttranscriptional regulation of utrophin by miR-206. The assay has a Z′ of 0.7, indicating robust performance in high-throughput format. This assay can be used to study utrophin regulatory mechanisms or to screen chemical libraries for compounds that upregulate utrophin posttranscriptionally via its UTRs. Compounds identified via this assay, used alone or in a synergistic combination with utrophin promoter-targeting molecules, would be predicted to have therapeutic potential for DMD.
4
Fabbrizio, E., J. Latouche, F. Rivier, G. Hugon, and D. Mornet. "Re-evaluation of the distributions of dystrophin and utrophin in sciatic nerve." Biochemical Journal 312, no. 1 (November 15, 1995): 309–14. http://dx.doi.org/10.1042/bj3120309.
Differential expression of proteins belonging to the dystrophin family was analysed in peripheral nerves. In agreement with previous reports, no full-size dystrophin was detectable, only Dp116, one of the short dystrophin products of the Duchenne muscular dystrophy (DMD) gene. We used specific monoclonal antibodies to fully investigate the presence of utrophin, a dystrophin homologue encoded by a gene located on chromosome 6q24. Evidence is presented here of the presence of two potential isoforms of full-length utrophin in different nerve structures, which may differ by alternative splicing of the 3′-terminal part of the utrophin gene according to the specificities of the monoclonal antiobodies used. One full-length utrophin was co-localized with Dp116 in the sheath around each separate Schwann cell-axon unit, but the other utrophin isoform was found to be perineurium-specific. We also highlighted a potential 80 kDa utrophin-related protein. The utrophin distribution in peripheral nerves was re-evaluated and utrophin isoforms were detected at the protein level. This preliminary indication will require more concrete molecular evidence to confirm the presence of these two utrophin isoforms as well as the potential 80 kDa utrophin isoform, but the results strongly suggest that each isoform must have a specialized role and function within each specific nervous structure.
5
Khurana, Tejvir S., Alan G. Rosmarin, Jing Shang, Thomas O. B. Krag, Saumya Das, and Steen Gammeltoft. "Activation of Utrophin Promoter by Heregulin via theets-related Transcription Factor Complex GA-binding Protein α/β." Molecular Biology of the Cell 10, no. 6 (June 1999): 2075–86. http://dx.doi.org/10.1091/mbc.10.6.2075.
Utrophin/dystrophin-related protein is the autosomal homologue of the chromosome X-encoded dystrophin protein. In adult skeletal muscle, utrophin is highly enriched at the neuromuscular junction. However, the molecular mechanisms underlying regulation of utrophin gene expression are yet to be defined. Here we demonstrate that the growth factor heregulin increases de novo utrophin transcription in muscle cell cultures. Using mutant reporter constructs of the utrophin promoter, we define the N-box region of the promoter as critical for heregulin-mediated activation. Using this region of the utrophin promoter for DNA affinity purification, immunoblots, in vitro kinase assays, electrophoretic mobility shift assays, and in vitro expression in cultured muscle cells, we demonstrate thatets-related GA-binding protein α/β transcription factors are activators of the utrophin promoter. Taken together, these results suggest that the GA-binding protein α/β complex of transcription factors binds and activates the utrophin promoter in response to heregulin-activated extracellular signal–regulated kinase in muscle cell cultures. These findings suggest methods for achieving utrophin up-regulation in Duchenne’s muscular dystrophy as well as mechanisms by which neurite-derived growth factors such as heregulin may influence the regulation of utrophin gene expression and subsequent enrichment at the neuromuscular junction of skeletal muscle.
6
MORRIS, Glenn E., Nguyen thi MAN, Nguyen thi Ngoc HUYEN, Alexander PEREBOEV, John KENDRICK-JONES, and Steven J. WINDER. "Disruption of the utrophin–actin interaction by monoclonal antibodies and prediction of an actin-binding surface of utrophin." Biochemical Journal 337, no. 1 (December 17, 1998): 119–23. http://dx.doi.org/10.1042/bj3370119.
Monoclonal antibody (mAb) binding sites in the N-terminal actin-binding domain of utrophin have been identified using phage-displayed peptide libraries, and the mAbs have been used to probe functional regions of utrophin involved in actin binding. mAbs were characterized for their ability to interact with the utrophin actin-binding domain and to affect actin binding to utrophin in sedimentation assays. One of these antibodies was able to inhibit utrophin–F-actin binding and was shown to recognize a predicted helical region at residues 13–22 of utrophin, close to a previously predicted actin-binding site. Two other mAbs which did not affect actin binding recognized predicted loops in the second calponin homology domain of the utrophin actin-binding domain. Using the known three-dimensional structure of the homologous actin-binding domain of fimbrin, these results have enabled us to determine the likely orientation of the utrophin actin-binding domain with respect to the actin filament.
7
James, M., A. Nuttall, J. L. Ilsley, K. Ottersbach, J. M. Tinsley, M. Sudol, and S. J. Winder. "Adhesion-dependent tyrosine phosphorylation of (beta)-dystroglycan regulates its interaction with utrophin." Journal of Cell Science 113, no. 10 (May 15, 2000): 1717–26. http://dx.doi.org/10.1242/jcs.113.10.1717.
Many cell adhesion-dependent processes are regulated by tyrosine phosphorylation. In order to investigate the role of tyrosine phosphorylation of the utrophin-dystroglycan complex we treated suspended or adherent cultures of HeLa cells with peroxyvanadate and immunoprecipitated (beta)-dystroglycan and utrophin from cell extracts. Western blotting of (β)-dystroglycan and utrophin revealed adhesion- and peroxyvanadate-dependent mobility shifts which were recognised by anti-phospho-tyrosine antibodies. Using maltose binding protein fusion constructs to the carboxy-terminal domains of utrophin we were able to demonstrate specific interactions between the WW, EF and ZZ domains of utrophin and (beta)-dystroglycan by co-immunoprecipitation with endogenous (beta)-dystroglycan. In extracts from cells treated with peroxyvanadate, where endogenous (beta)-dystroglycan was tyrosine phosphorylated, (beta)-dystroglycan was no longer co-immunoprecipitated with utrophin fusion constructs. Peptide ‘SPOTs’ assays confirmed that tyrosine phosphorylation of (beta)-dystroglycan regulated the binding of utrophin. The phosphorylated tyrosine was identified as Y(892) in the (beta)-dystroglycan WW domain binding motif PPxY thus demonstrating the physiological regulation of the (beta)-dystroglycan/utrophin interaction by adhesion-dependent tyrosine phosphorylation.
8
Winder, S. J., L. Hemmings, S. K. Maciver, S. J. Bolton, J. M. Tinsley, K. E. Davies, D. R. Critchley, and J. Kendrick-Jones. "Utrophin actin binding domain: analysis of actin binding and cellular targeting." Journal of Cell Science 108, no. 1 (January 1, 1995): 63–71. http://dx.doi.org/10.1242/jcs.108.1.63.
Utrophin, or dystrophin-related protein, is an autosomal homologue of dystrophin. The protein is apparently ubiquitously expressed and in muscle tissues the expression is developmentally regulated. Since utrophin has a similar domain structure to dystrophin it has been suggested that it could substitute for dystrophin in dystrophic muscle. Like dystrophin, utrophin has been shown to be associated with a membrane-bound glycoprotein complex. Here we demonstrate that expressed regions of the predicted actin binding domain in the NH2 terminus of utrophin are able to bind to F-actin in vitro, but do not interact with G-actin. The utrophin actin binding domain was also able to associate with actin-containing structures, stress fibres and focal contacts, when microinjected into chick embryo fibroblasts. The expressed NH2-terminal 261 amino acid domain of utrophin has an affinity for skeletal F-action (Kd 19 +/- 2.8 microM), midway between that of the corresponding domains of alpha-actinin (Kd 4 microM) and dystrophin (Kd 44 microM). Moreover, this utrophin domain binds to non-muscle actin with a approximately 4-fold higher affinity than to skeletal muscle actin. These data (together with those of Matsumura et al. (1992) Nature, 360, 588–591) demonstrate for the first time that utrophin is capable of performing a functionally equivalent role to that of dystrophin. The NH2 terminus of utrophin binds to actin and the COOH terminus binds to the membrane associated glycoprotein complex, thus in non-muscle and developing muscle utrophin performs the same predicted ‘spacer’ or ‘shock absorber’ role as dystrophin in mature muscle tissues. These data suggest that utrophin could replace dystrophin functionally in dystrophic muscle.
Gramolini, Anthony O., Guy Bélanger, and Bernard J. Jasmin. "Distinct regions in the 3′ untranslated region are responsible for targeting and stabilizing utrophin transcripts in skeletal muscle cells." Journal of Cell Biology 154, no. 6 (September 10, 2001): 1173–84. http://dx.doi.org/10.1083/jcb.200101108.
In this study, we have sought to determine whether utrophin transcripts are targeted to a distinct subcellular compartment in skeletal muscle cells, and have examined the role of the 3′ untranslated region (UTR) in regulating the stability and localization of utrophin transcripts. Our results show that utrophin transcripts associate preferentially with cytoskeleton-bound polysomes via actin microfilaments. Because this association is not evident in myoblasts, our findings also indicate that the localization of utrophin transcripts with cytoskeleton-bound polysomes is under developmental influences. Transfection of LacZ reporter constructs containing the utrophin 3′UTR showed that this region is critical for targeting chimeric mRNAs to cytoskeleton-bound polysomes and controlling transcript stability. Deletion studies resulted in the identification of distinct regions within the 3′UTR responsible for targeting and stabilizing utrophin mRNAs. Together, these results illustrate the contribution of posttranscriptional events in the regulation of utrophin in skeletal muscle. Accordingly, these findings provide novel targets, in addition to transcriptional events, for which pharmacological interventions may be envisaged to ultimately increase the endogenous levels of utrophin in skeletal muscle fibers from Duchenne muscular dystrophy (DMD) patients.
The spectrin superfamily is a diverse group of proteins variously involved in cross- linking, bundling and binding to the F-actin cytoskeleton. These proteins are modular in nature and interaction with actin occurs, at least in part, via CH domain containing ABDs. The actin binding domains of the spectrin superfamily proteins are all very similar in overall structure however the functions of the individual proteins differ greatly. Utrophin is a member of the spectrin superfamily and has been used extensively to investigate and model the association of actin-binding domains with F- actin; however, much controversy exists as to whether binding occurs when the domain is in an open or a closed conformation. The data herein specifically investigates the importance of the utrophin ABD inter- CH domain linker to the conformation of the domain and how this domain associates with F-actin. We provide evidence that this particular region of the ABD is particularly sensitive to mutation and that the conformation of the domain when in solution cannot be altered by affecting the electrostatic environment surrounding the protein. It has been assumed previously that the utrophin ABD adopts a closed and compact configuration in solution similar to the fimbrin crystal structure conformation; however we present evidence that suggests this is not the case. It has been proposed that the utrophin ABD may open from this closed conformation to bind F-actin in a more open manner, we present data that demonstrates that opening of the domain is not essential to F-actin binding and that there is very little conformation change associated with the domain upon interaction with F-actin. It appears that the utrophin ABD can bind F actin in two conformations. This supports current models of utrophin ABD binding where interaction with F-actin occurs in either an open or closed conformation. The data presented here provides an interesting insight into the utrophin ABD/F-actin interaction and raises many questions regarding the evaluation of current binding models. Future research stemming from this work will serve to further the understanding of how utrophin and related actin-binding proteins interact with F-actin.
2
Dennis, Carina Louise. "Promoter studies of the utrophin gene." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.320271.
Pearce, Marcela. "Genomic structure of the human utrophin gene." Thesis, University of Oxford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318897.
Fisher, Rosie. "Utrophin in therapy of Duchenne muscular distrophy." Thesis, University of Oxford, 2001. http://ora.ox.ac.uk/objects/uuid:192fbccd-d037-4ce8-b1cd-0315afe1860d.
James, Marian. "Monoclonal antibody studies of dystrophin and utrophin." Thesis, University of Salford, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360455.
Moores, Carolyn Ann. "Structure-function analysis of the utrophin actin binding domain." Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624459.
Coriati, Adèle. "Skeletal Muscle Specific IRES Activity of Utrophin A Is Enhanced by Eef1a2." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/19866.
Understanding the regulatory mechanisms controlling utrophin A expression at the sarcolemma of dystrophic muscles will facilitate the development of therapeutic strategies to ameliorate the pathophysiological features of Duchenne Muscular Dystrophy (DMD). The main goal of this study was to characterize the regulation of utrophin A IRES activity using a transgenic mouse model expressing the utrophin A 5’UTR bicistronic reporter and to identify trans-acting factors that could mediate IRES activity and endogenous expression of utrophin A. We found that utrophin A IRES activity is specifically expressed in skeletal muscles. Moreover, we identified eEF1A2 as a muscle-specific trans-acting factor that can interact with utrophin A and mediate IRES-dependent translation of utrophin A. Finally, we showed that eEF1A2 mediates endogenous utrophin A expression and localization in skeletal muscle. Identifying pharmacological compounds that would specifically target eEF1A2 and increase endogenous levels of utrophin A expression could serve as a drug-based therapy to treat DMD.
8
Péladeau, Christine. "Utrophin A Upregulation by FDA-Approved Drugs for the Treatment of Duchenne Muscular Dystrophy." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/39298.
Duchenne Muscular Dystrophy (DMD) is a disorder caused by mutations in the dystrophin gene, preventing the production of the functional dystrophin protein which assures maintenance of the myofiber integrity throughout muscle contraction. A lack of dystrophin results in severe muscle degeneration and regeneration accompanied by a loss of muscle function. Many pre-clinical and clinical studies are focused on developing strategies to counteract the detrimental effects of DMD; however, there is no cure. One such approach consists of upregulating the endogenous protein utrophin A in dystrophic muscle, which, once highly expressed at the sarcolemma, could functionally compensate for the lack of dystrophin. Recent evidence demonstrates that utrophin A expression is regulated at its 3’ and 5’UTR through post-transcriptional and translational events. Therefore, in the work presented here, we hypothesized that repurposing FDA-approved drugs that target the signaling pathways involved in post-transcriptional and translational regulation of utrophin A will be an efficient approach in rapidly bringing new therapeutic interventions for DMD.
In this work, we repurposed four promising FDA-approved drugs able to stimulate utrophin A expression levels in dystrophic muscles: the anti-coagulant drug Heparin, the anti-inflammatory drug Celecoxib, the β-adrenergic receptor blocking agent Betaxolol and the cholesterol-lowering drug Pravastatin. These drugs induce significant improvements in the dystrophic phenotype of mdx mice. This includes amelioration of muscle fiber integrity and muscle function as well as promoting morphological and fiber type changes in mdx mice muscles. Collectively, this thesis describes the potential of a repurposing approach to activate key post-transcriptional and translational pathways involved in utrophin A’s regulation in the hopes of developing new therapeutics for the treatment of DMD.
9
Perkins, Kelly Joanne. "Molecular and functional analysis of the transcriptional regulation of utrophin." Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.270259.
Wilson, James Baillie. "Transcription of the utrophin gene : identification and characterisation of novel transcripts." Thesis, University College London (University of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392667.
Harrison, Mary-Ann. The molecular basis of Duchenne muscular dystrophy: Utrophin as a candidate for therapeutic intervention. Sudbury, Ont: Laurentian University, School of Graduate Studies, 2004.
"Utrophin: The Intersection Between Pharmacological and Genetic Therapy." In Duchenne Muscular Dystrophy, 279–306. CRC Press, 2006. http://dx.doi.org/10.3109/9780849374456-15.
"Utrophin in the Therapy of Duchenne M uscular D ystrophy." In Molecular Mechanisms of Muscular Dystrophies, 53–66. CRC Press, 2006. http://dx.doi.org/10.1201/9781498713962-8.
Bell, Brett J., and Sherry L. Voytik-Harbin. "Multiaxial Study of Fibroblast Biomechanics in a 3D Collagen Matrix." In ASME 2009 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2009. http://dx.doi.org/10.1115/sbc2009-206722.
It is becoming increasingly evident, that of the signaling modalities relevant to the cell-extracellular matrix (ECM) microenvironment, the mechanical component is a very important mediator of cell behavior (reviewed in [1, 2]). Indeed, proliferation, ECM protein expression (collagen), matrix metalloproteinase (MMP) levels, migration, and stem cell differentiation, have all been shown to be affected by mechanical environmental cues [3, 4]. Although the importance of physical signaling mechanisms has been well established, the bulk of this work has yet to be translated to a more physiologic 3D microenvironment [1]. Self-assembling collagen matrices provide a biochemically, biophysically relevant 3D model of soft tissues in which biomechanical studies can be performed [5, 6]. It is with this 3D tissue model in mind, that a biaxial mechanical testing system (BMTS) was devised, built, tested, and applied to the study of cell-ECM biomechanics. The completion of this device has enabled us, to undertake a multi-scale, multidimensional study of cell-ECM mechanics. Hierarchical quantification of cell and ECM strains using digital image correlation (DIC) facilitate a more complete understanding of the mechanical response of cells to macroscopic loads and deformations. Furthermore, transfection of cells with GFP tagged actin binding protein utrophin (UTR-GFP) enables qualitative assessment of cytoskeletal deformations [7].
2
Eldor, A., M. Bar-Ner, L. Wasserman, Y. matzner, Z. Fuks, and I. Viodavsky. "HEPARIN AND NON-ANTICOAGULANT HEPARINS INHIBIT HEPARANASE ACTIVITY IN NORMAL AND MALIGNANT CELLS:POSSIBLE THERAPEUTIC USE IN PREVENTION OF EXTRAVASATION AND DISSEMINATION OF BLOOD BORNE CELLS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643664.
Degradation of vascular subendothelium occurs in_vivo during the process of inflammation and tumor invasion. Various observations suggest that the capacity of some blood-borne cells to extravasate may depend in part on their ability to express hepara-nase activity. Incubation of human platelets, human nc-utrophils, or highly metastatic mouse lymphoma cells with sulfate-labeled extracellular matrix (ECM) results in heparanase mediated release of labeled heparan sulfate cleavage fragments (0.5<Kav<0.85 on Sepharose 5B) (J. Clin.Invest. 74: 1842 and 76: 1306; Cancer Res. 43: 2704). The present study was undertaken to test the heparanase inhibitory effect of heparin and non-anticoagulant species of heparin that might havea potential therapeutic use in preventing heparanase mediated extravasation ofblood-borne cells. We prepared totallyor N-desulfated heparins which were either left with their N-position exposed or were subsequently N-acetylated or N-resulfated. These heparins exhibited less than 5% of the anticoagulant activityof native heparin. It was found that total desulfation of heparin abolished its heparanase inhibitory activity whether desulfation was followed by N-acetylation or not. Inhibitory effect was restored by resulfation of the N-position. When only the N-sulfate group was desulfated, inhibitory activity was lost but could be restored by acetylation of the N-position. These results indicate that N-sulfate groups of heparin are necessary for its heparanase inhibitory activity but can be substituted by an acetyl group provided that the 0-sulfate groups are retained. Low Mr heparins (main Mr species of 2500 and 4500 daltons) and heparin fragments as small as the tetrasaccharide inhibited degradation of heparan sulfate in the ECM, albeit to a lower extent than native heparin. Similar effects of the different heparins were observed with heparanase activities from platelets, neutrophils and lymphoma cells. Preliminary in vivo experiments suggest that non-anticoagulant heparins interfere with tumor metastasis and experimental autoimmune diseases (some heparins were kindly provided by Inst. Choay, Paris and Kabi Vitrum, Stockholm).
