Zeitschriftenartikel: „Utrophin“

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Marshall, Jamie L., Johan Holmberg, Eric Chou, Amber C. Ocampo, Jennifer Oh, Joy Lee, Angela K. Peter, Paul T. Martin und Rachelle H. Crosbie-Watson. „Sarcospan-dependent Akt activation is required for utrophin expression and muscle regeneration“. Journal of Cell Biology 197, Nr. 7 (25.06.2012): 1009–27. http://dx.doi.org/10.1083/jcb.201110032.

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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.

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Perkins, Kelly J., Utpal Basu, Murat T. Budak, Caroline Ketterer, Santhosh M. Baby, Olga Lozynska, John A. Lunde, Bernard J. Jasmin, Neal A. Rubinstein und Tejvir S. Khurana. „Ets-2 Repressor Factor Silences Extrasynaptic Utrophin by N-Box–mediated Repression in Skeletal Muscle“. Molecular Biology of the Cell 18, Nr. 8 (August 2007): 2864–72. http://dx.doi.org/10.1091/mbc.e06-12-1069.

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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.

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Moorwood, Catherine, Neha Soni, Gopal Patel, Steve D. Wilton und Tejvir S. Khurana. „A Cell-Based High-Throughput Screening Assay for Posttranscriptional Utrophin Upregulation“. Journal of Biomolecular Screening 18, Nr. 4 (30.10.2012): 400–406. http://dx.doi.org/10.1177/1087057112465648.

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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.

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Fabbrizio, E., J. Latouche, F. Rivier, G. Hugon und D. Mornet. „Re-evaluation of the distributions of dystrophin and utrophin in sciatic nerve“. Biochemical Journal 312, Nr. 1 (15.11.1995): 309–14. http://dx.doi.org/10.1042/bj3120309.

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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.

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Khurana, Tejvir S., Alan G. Rosmarin, Jing Shang, Thomas O. B. Krag, Saumya Das und 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, Nr. 6 (Juni 1999): 2075–86. http://dx.doi.org/10.1091/mbc.10.6.2075.

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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.

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MORRIS, Glenn E., Nguyen thi MAN, Nguyen thi Ngoc HUYEN, Alexander PEREBOEV, John KENDRICK-JONES und Steven J. WINDER. „Disruption of the utrophin–actin interaction by monoclonal antibodies and prediction of an actin-binding surface of utrophin“. Biochemical Journal 337, Nr. 1 (17.12.1998): 119–23. http://dx.doi.org/10.1042/bj3370119.

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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.

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James, M., A. Nuttall, J. L. Ilsley, K. Ottersbach, J. M. Tinsley, M. Sudol und S. J. Winder. „Adhesion-dependent tyrosine phosphorylation of (beta)-dystroglycan regulates its interaction with utrophin“. Journal of Cell Science 113, Nr. 10 (15.05.2000): 1717–26. http://dx.doi.org/10.1242/jcs.113.10.1717.

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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.

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Winder, S. J., L. Hemmings, S. K. Maciver, S. J. Bolton, J. M. Tinsley, K. E. Davies, D. R. Critchley und J. Kendrick-Jones. „Utrophin actin binding domain: analysis of actin binding and cellular targeting“. Journal of Cell Science 108, Nr. 1 (01.01.1995): 63–71. http://dx.doi.org/10.1242/jcs.108.1.63.

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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.

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Dubowitz, Victor. „Utrophin euphoria“. Neuromuscular Disorders 7, Nr. 1 (Januar 1997): 5–6. http://dx.doi.org/10.1016/s0960-8966(96)00432-4.

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Gramolini, Anthony O., Guy Bélanger und 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, Nr. 6 (10.09.2001): 1173–84. http://dx.doi.org/10.1083/jcb.200101108.

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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.

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Guiraud, Simon, Benjamin Edwards, Arran Babbs, Sarah E. Squire, Adam Berg, Lee Moir, Matthew J. Wood und Kay E. Davies. „The potential of utrophin and dystrophin combination therapies for Duchenne muscular dystrophy“. Human Molecular Genetics 28, Nr. 13 (05.03.2019): 2189–200. http://dx.doi.org/10.1093/hmg/ddz049.

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Abstract Duchenne muscular dystrophy (DMD) is a lethal neuromuscular disorder caused by loss of dystrophin. Several therapeutic modalities are currently in clinical trials but none will achieve maximum functional rescue and full disease correction. Therefore, we explored the potential of combining the benefits of dystrophin with increases of utrophin, an autosomal paralogue of dystrophin. Utrophin and dystrophin can be co-expressed and co-localized at the same muscle membrane. Wild-type (wt) levels of dystrophin are not significantly affected by a moderate increase of utrophin whereas higher levels of utrophin reduce wt dystrophin, suggesting a finite number of actin binding sites at the sarcolemma. Thus, utrophin upregulation strategies may be applied to the more mildly affected Becker patients with lower dystrophin levels. Whereas increased dystrophin in wt animals does not offer functional improvement, overexpression of utrophin in wt mice results in a significant supra-functional benefit over wt. These findings highlight an additive benefit of the combined therapy and potential new unique roles of utrophin. Finally, we show a 30% restoration of wt dystrophin levels, using exon-skipping, together with increased utrophin levels restores dystrophic muscle function to wt levels offering greater therapeutic benefit than either single approach alone. Thus, this combination therapy results in additive functional benefit and paves the way for potential future combinations of dystrophin- and utrophin-based strategies.

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Gramolini, Anthony O., Guy Bélanger, Jennifer M. Thompson, Joe V. Chakkalakal und Bernard J. Jasmin. „Increased expression of utrophin in a slow vs. a fast muscle involves posttranscriptional events“. American Journal of Physiology-Cell Physiology 281, Nr. 4 (01.10.2001): C1300—C1309. http://dx.doi.org/10.1152/ajpcell.2001.281.4.c1300.

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In addition to showing differences in the levels of contractile proteins and metabolic enzymes, fast and slow muscles also differ in their expression profile of structural and synaptic proteins. Because utrophin is a structural protein expressed at the neuromuscular junction, we hypothesize that its expression may be different between fast and slow muscles. Western blots showed that, compared with fast extensor digitorum longus (EDL) muscles, slow soleus muscles contain significantly more utrophin. Quantitative RT-PCR revealed that this difference is accompanied by a parallel increase in the expression of utrophin transcripts. Interestingly, the higher levels of utrophin and its mRNA appear to occur in extrasynaptic regions of muscle fibers as shown by immunofluorescence and in situ hybridization experiments. Furthermore, nuclear run-on assays showed that the rate of transcription of the utrophin gene was nearly identical between EDL and soleus muscles, indicating that increased mRNA stability accounts for the higher levels of utrophin in slow muscles. Direct plasmid injections of reporter gene constructs showed that cis-acting elements contained within the utrophin 3′-untranslated region (3′-UTR) confer greater stability to chimeric LacZ transcripts in soleus muscles. Finally, we observed a clear difference between EDL and soleus muscles in the abundance of RNA-binding proteins interacting with the utrophin 3′-UTR. Together, these findings highlight the contribution of posttranscriptional events in regulating the expression of utrophin in muscle.

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Bonet-Kerrache, Armelle, Mathieu Fortier, Franck Comunale und Cécile Gauthier-Rouvière. „The GTPase RhoA increases utrophin expression and stability, as well as its localization at the plasma membrane“. Biochemical Journal 391, Nr. 2 (10.10.2005): 261–68. http://dx.doi.org/10.1042/bj20050024.

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The Rho family of small GTPases are signalling molecules involved in cytoskeleton remodelling and gene transcription. Their activities are important for many cellular processes, including myogenesis. In particular, RhoA positively regulates skeletal-muscle differentiation. We report in the present study that the active form of RhoA increases the expression of utrophin, the autosomal homologue of dystrophin in the mouse C2C12 and rat L8 myoblastic cell lines. Even though this RhoA-dependent utrophin increase is higher in proliferating myoblasts, it is maintained during myogenic differentiation. This occurs via two mechanisms: (i) transcriptional activation of the utrophin promoter A and (ii) post-translational stabilization of utrophin. In addition, RhoA increases plasma-membrane localization of utrophin. Thus RhoA activation up-regulates utrophin levels and enhances its localization at the plasma membrane.

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Deconinck, Anne E., Allyson C. Potter, Jonathon M. Tinsley, Sarah J. Wood, Ruth Vater, Carol Young, Laurent Metzinger, Angela Vincent, Clarke R. Slater und Kay E. Davies. „Postsynaptic Abnormalities at the Neuromuscular Junctions of Utrophin-deficient Mice“. Journal of Cell Biology 136, Nr. 4 (24.02.1997): 883–94. http://dx.doi.org/10.1083/jcb.136.4.883.

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Utrophin is a dystrophin-related cytoskeletal protein expressed in many tissues. It is thought to link F-actin in the internal cytoskeleton to a transmembrane protein complex similar to the dystrophin protein complex (DPC). At the adult neuromuscular junction (NMJ), utrophin is precisely colocalized with acetylcholine receptors (AChRs) and recent studies have suggested a role for utrophin in AChR cluster formation or maintenance during NMJ differentiation. We have disrupted utrophin expression by gene targeting in the mouse. Such mice have no utrophin detectable by Western blotting or immunocytochemistry. Utrophindeficient mice are healthy and show no signs of weakness. However, their NMJs have reduced numbers of AChRs (α-bungarotoxin [α-BgTx] binding reduced to ∼60% normal) and decreased postsynaptic folding, though only minimal electrophysiological changes. Utrophin is thus not essential for AChR clustering at the NMJ but may act as a component of the postsynaptic cytoskeleton, contributing to the development or maintenance of the postsynaptic folds. Defects of utrophin could underlie some forms of congenital myasthenic syndrome in which a reduction of postsynaptic folds is observed.

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Rybakova, Inna N., Jitandrakumar R. Patel, Kay E. Davies, Peter D. Yurchenco und James M. Ervasti. „Utrophin Binds Laterally along Actin Filaments and Can Couple Costameric Actin with Sarcolemma When Overexpressed in Dystrophin-deficient Muscle“. Molecular Biology of the Cell 13, Nr. 5 (Mai 2002): 1512–21. http://dx.doi.org/10.1091/mbc.01-09-0446.

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Dystrophin is widely thought to mechanically link the cortical cytoskeleton with the muscle sarcolemma. Although the dystrophin homolog utrophin can functionally compensate for dystrophin in mice, recent studies question whether utrophin can bind laterally along actin filaments and anchor filaments to the sarcolemma. Herein, we have expressed full-length recombinant utrophin and show that the purified protein is fully soluble with a native molecular weight and molecular dimensions indicative of monomers. We demonstrate that like dystrophin, utrophin can form an extensive lateral association with actin filaments and protect actin filaments from depolymerization in vitro. However, utrophin binds laterally along actin filaments through contribution of acidic spectrin-like repeats rather than the cluster of basic repeats used by dystrophin. We also show that the defective linkage between costameric actin filaments and the sarcolemma in dystrophin-deficientmdx muscle is rescued by overexpression of utrophin. Our results demonstrate that utrophin and dystrophin are functionally interchangeable actin binding proteins, but that the molecular epitopes important for filament binding differ between the two proteins. More generally, our results raise the possibility that spectrin-like repeats may enable some members of the plakin family of cytolinkers to laterally bind and stabilize actin filaments.

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Yamane, Akira, Satonari Akutsu, Thomas G. H. Diekwisch und Ryoichi Matsuda. „Satellite cells and utrophin are not directly correlated with the degree of skeletal muscle damage in mdx mice“. American Journal of Physiology-Cell Physiology 289, Nr. 1 (Juli 2005): C42—C48. http://dx.doi.org/10.1152/ajpcell.00577.2004.

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To determine whether muscle satellite cells and utrophin are correlated with the degree of damage in mdx skeletal muscles, we measured the area of the degenerative region as an indicator of myofiber degeneration in the masseter, gastrocnemius, soleus, and diaphragm muscles of mdx mice. Furthermore, we analyzed the expression levels of the paired box homeotic gene 7 ( pax7), m-cadherin (the makers of muscle satellite cells), and utrophin mRNA. We also investigated the immunolocalization of m-cadherin and utrophin proteins in the muscles of normal C57BL/10J (B10) and mdx mice. The expression level of pax7 mRNA and the percentage of m-cadherin-positive cells among the total number of cell nuclei in the muscle tissues in all four muscles studied were greater in the mdx mice than in the B10 mice. However, there was no significant correlation between muscle damage and expression level for pax7 mRNA ( R = −0.140), nor was there a correlation between muscle damage and the percentage of satellite cells among the total number of cell nuclei ( R = −0.411) in the mdx mice. The expression level of utrophin mRNA and the intensity of immunostaining for utrophin in all four muscles studied were greater in the mdx mice than in the B10 mice. However, there also was not a significant correlation between muscle damage and expression level of utrophin mRNA ( R = 0.231) in the mdx mice, although upregulated utrophin was incorporated into the sarcolemma. These results suggest that satellite cells and utrophin are not directly correlated with the degree of skeletal muscle damage in mdx mice.

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Angus, Lindsay M., Joe V. Chakkalakal, Alexandre Méjat, Joe K. Eibl, Guy Bélanger, Lynn A. Megeney, Eva R. Chin, Laurent Schaeffer, Robin N. Michel und Bernard J. Jasmin. „Calcineurin-NFAT signaling, together with GABP and peroxisome PGC-1α, drives utrophin gene expression at the neuromuscular junction“. American Journal of Physiology-Cell Physiology 289, Nr. 4 (Oktober 2005): C908—C917. http://dx.doi.org/10.1152/ajpcell.00196.2005.

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We examined whether calcineurin-NFAT (nuclear factors of activated T cells) signaling plays a role in specifically directing the expression of utrophin in the synaptic compartment of muscle fibers. Immunofluorescence experiments revealed the accumulation of components of the calcineurin-NFAT signaling cascade within the postsynaptic membrane domain of the neuromuscular junction. RT-PCR analysis using synaptic vs. extrasynaptic regions of muscle fibers confirmed these findings by showing an accumulation of calcineurin transcripts within the synaptic compartment. We also examined the effect of calcineurin on utrophin gene expression. Pharmacological inhibition of calcineurin in mice with either cyclosporin A or FK506 resulted in a marked decrease in utrophin A expression at synaptic sites, whereas constitutive activation of calcineurin had the opposite effect. Mutation of the previously identified NFAT binding site in the utrophin A promoter region, followed by direct gene transfer studies in mouse muscle, led to an inhibition in the synaptic expression of a lacZ reporter gene construct. Transfection assays performed with cultured myogenic cells indicated that calcineurin acted additively with GA binding protein (GABP) to transactivate utrophin A gene expression. Because both GABP- and calcineurin-mediated pathways are targeted by peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), we examined whether this coactivator contributes to utrophin gene expression. In vitro and in vivo transfection experiments showed that PGC-1α alone induces transcription from the utrophin A promoter. Interestingly, this induction is largely potentiated by coexpression of PGC-1α with GABP. Together, these studies indicate that the synaptic expression of utrophin is also driven by calcineurin-NFAT signaling and occurs in conjunction with signaling events that involve GABP and PGC-1α.

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Grady, R. Mark, John P. Merlie und Joshua R. Sanes. „Subtle Neuromuscular Defects in Utrophin-deficient Mice“. Journal of Cell Biology 136, Nr. 4 (24.02.1997): 871–82. http://dx.doi.org/10.1083/jcb.136.4.871.

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Utrophin is a large cytoskeletal protein that is homologous to dystrophin, the protein mutated in Duchenne and Becker muscular dystrophy. In skeletal muscle, dystrophin is broadly distributed along the sarcolemma whereas utrophin is concentrated at the neuromuscular junction. This differential localization, along with studies on cultured cells, led to the suggestion that utrophin is required for synaptic differentiation. In addition, utrophin is present in numerous nonmuscle cells, suggesting that it may have a more generalized role in the maintenance of cellular integrity. To test these hypotheses we generated and characterized utrophin-deficient mutant mice. These mutant mice were normal in appearance and behavior and showed no obvious defects in muscle or nonmuscle tissue. Detailed analysis, however, revealed that the density of acetylcholine receptors and the number of junctional folds were reduced at the neuromuscular junctions in utrophin-deficient skeletal muscle. Despite these subtle derangements, the overall structure of the mutant synapse was qualitatively normal, and the specialized characteristics of the dystrophin-associated protein complex were preserved at the mutant neuromuscular junction. These results point to a predominant role for other molecules in the differentiation and maintenance of the postsynaptic membrane.

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Wells, William A. „Sticky utrophin messages“. Journal of Cell Biology 154, Nr. 6 (10.09.2001): 1098. http://dx.doi.org/10.1083/jcb1546iti4.

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Fulmer, Tim. „Biglycan meets utrophin“. Science-Business eXchange 4, Nr. 5 (Februar 2011): 122. http://dx.doi.org/10.1038/scibx.2011.122.

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Peters, Matthew F., Hélène M. Sadoulet-Puccio, R. Mark Grady, Neal R. Kramarcy, Louis M. Kunkel, Joshua R. Sanes, Robert Sealock und Stanley C. Froehner. „Differential Membrane Localization and Intermolecular Associations of α-Dystrobrevin Isoforms in Skeletal Muscle“. Journal of Cell Biology 142, Nr. 5 (07.09.1998): 1269–78. http://dx.doi.org/10.1083/jcb.142.5.1269.

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α-Dystrobrevin is both a dystrophin homologue and a component of the dystrophin protein complex. Alternative splicing yields five forms, of which two predominate in skeletal muscle: full-length α-dystrobrevin-1 (84 kD), and COOH-terminal truncated α-dystrobrevin-2 (65 kD). Using isoform-specific antibodies, we find that α-dystrobrevin-2 is localized on the sarcolemma and at the neuromuscular synapse, where, like dystrophin, it is most concentrated in the depths of the postjunctional folds. α-Dystrobrevin-2 preferentially copurifies with dystrophin from muscle extracts. In contrast, α-dystrobrevin-1 is more highly restricted to the synapse, like the dystrophin homologue utrophin, and preferentially copurifies with utrophin. In yeast two-hybrid experiments and coimmunoprecipitation of in vitro–translated proteins, α-dystrobrevin-2 binds dystrophin, whereas α-dystrobrevin-1 binds both dystrophin and utrophin. α-Dystrobrevin-2 was lost from the nonsynaptic sarcolemma of dystrophin-deficient mdx mice, but was retained on the perisynaptic sarcolemma even in mice lacking both utrophin and dystrophin. In contrast, α-dystrobrevin-1 remained synaptically localized in mdx and utrophin-negative muscle, but was absent in double mutants. Thus, the distinct distributions of α-dystrobrevin-1 and -2 can be partly explained by specific associations with utrophin and dystrophin, but other factors are also involved. These results show that alternative splicing confers distinct properties of association on the α-dystrobrevins.

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Peter, Angela K., Jamie L. Marshall und Rachelle H. Crosbie. „Sarcospan reduces dystrophic pathology: stabilization of the utrophin–glycoprotein complex“. Journal of Cell Biology 183, Nr. 3 (03.11.2008): 419–27. http://dx.doi.org/10.1083/jcb.200808027.

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Mutations in the dystrophin gene cause Duchenne muscular dystrophy and result in the loss of dystrophin and the entire dystrophin–glycoprotein complex (DGC) from the sarcolemma. We show that sarcospan (SSPN), a unique tetraspanin-like component of the DGC, ameliorates muscular dystrophy in dystrophin-deficient mdx mice. SSPN stabilizes the sarcolemma by increasing levels of the utrophin–glycoprotein complex (UGC) at the extrasynaptic membrane to compensate for the loss of dystrophin. Utrophin is normally restricted to the neuromuscular junction, where it replaces dystrophin to form a functionally analogous complex. SSPN directly interacts with the UGC and functions to stabilize utrophin protein without increasing utrophin transcription. These findings reveal the importance of protein stability in the prevention of muscular dystrophy and may impact the future design of therapeutics for muscular dystrophies.

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Onori, Annalisa, Agata Desantis, Serena Buontempo, Maria Grazia Di Certo, Maurizio Fanciulli, Luisa Salvatori, Claudio Passananti und Nicoletta Corbi. „The artificial 4-zinc-finger protein Bagly binds human utrophin promoter A at the endogenous chromosomal site and activates transcription“. Biochemistry and Cell Biology 85, Nr. 3 (Juni 2007): 358–65. http://dx.doi.org/10.1139/o07-015.

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Our aim is to upregulate the expression of the dystrophin-related gene utrophin in Duchenne muscular dystrophy, in this way complementing the lack of dystrophin function. To achieve utrophin upregulation, we designed and engineered synthetic zinc-inger based transcription factors. We have previously shown that the artificial 3-zinc-finger protein Jazz, fused with the appropriate effector domain, is able to drive the transcription of a test gene from utrophin promoter A. Here we report a novel artificial 4-zinc-finger protein, Bagly, which binds with optimized affinity–specificity to a 12 bp DNA target sequence that is internal to human utrophin promoter A. Bagly was generated adding to Jazz protein an extra-fourth zinc finger, derived from transcription factor YY1. Importantly, the Bagly DNA target sequence is statistically present in the human genome only 210 times, about 60 fewer times than the 9 bp Jazz DNA target sequence. Thanks to its additional zinc-finger domain, Bagly protein shows enhanced transcriptional activity. Moreover, we demonstrated Bagly's effective access and binding to active chromatin in the chromosomal context and its ability to upregulate endogenous utrophin.

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Porter, J. D., J. A. Rafael, R. J. Ragusa, J. K. Brueckner, J. I. Trickett und K. E. Davies. „The sparing of extraocular muscle in dystrophinopathy is lost in mice lacking utrophin and dystrophin“. Journal of Cell Science 111, Nr. 13 (01.07.1998): 1801–11. http://dx.doi.org/10.1242/jcs.111.13.1801.

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The extraocular muscles are one of few skeletal muscles that are structurally and functionally intact in Duchenne muscular dystrophy. Little is known about the mechanisms responsible for differential sparing or targeting of muscle groups in neuromuscular disease. One hypothesis is that constitutive or adaptive properties of the unique extraocular muscle phenotype may underlie their protection in dystrophinopathy. We assessed the status of extraocular muscles in the mdx mouse model of muscular dystrophy. Mice showed mild pathology in accessory extraocular muscles, but no signs of pathology were evident in the principal extraocular muscles at any age. By immunoblotting, the extraocular muscles of mdx mice exhibited increased levels of a dystrophin analog, dystrophin-related protein or utrophin. These data suggest, but do not provide mechanistic evidence, that utrophin mediates eye muscle protection. To examine a potential causal relationship, knockout mouse models were used to determine whether eye muscle sparing could be reversed. Mice lacking expression of utrophin alone, like the dystrophin-deficient mdx mouse, showed no pathological alterations in extraocular muscle. However, mice deficient in both utrophin and dystrophin exhibited severe changes in both the accessory and principal extraocular muscles, with the eye muscles affected more adversely than other skeletal muscles. Selected extraocular muscle fiber types still remained spared, suggesting the operation of an alternative mechanism for muscle sparing in these fiber types. We propose that an endogenous upregulation of utrophin is mechanistic in protecting extraocular muscle in dystrophinopathy. Moreover, data lend support to the hypothesis that interventions designed to increase utrophin levels may ameliorate the pathology in other skeletal muscles in Duchenne muscular dystrophy.

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Perronnet, Caroline, und Cyrille Vaillend. „Dystrophins, Utrophins, and Associated Scaffolding Complexes: Role in Mammalian Brain and Implications for Therapeutic Strategies“. Journal of Biomedicine and Biotechnology 2010 (2010): 1–19. http://dx.doi.org/10.1155/2010/849426.

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Two decades of molecular, cellular, and functional studies considerably increased our understanding of dystrophins function and unveiled the complex etiology of the cognitive deficits in Duchenne muscular dystrophy (DMD), which involves altered expression of several dystrophin-gene products in brain. Dystrophins are normally part of critical cytoskeleton-associated membrane-bound molecular scaffolds involved in the clustering of receptors, ion channels, and signaling proteins that contribute to synapse physiology and blood-brain barrier function. The utrophin gene also drives brain expression of several paralogs proteins, which cellular expression and biological roles remain to be elucidated. Here we review the structural and functional properties of dystrophins and utrophins in brain, the consequences of dystrophins loss-of-function as revealed by numerous studies in mouse models of DMD, and we discuss future challenges and putative therapeutic strategies that may compensate for the cognitive impairment in DMD based on experimental manipulation of dystrophins and/or utrophins brain expression.

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&NA;. „Utrophin in muscular dystrophy“. Inpharma Weekly &NA;, Nr. 1071 (Januar 1997): 7. http://dx.doi.org/10.2165/00128413-199710710-00015.

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Campbell, Kevin P., und Rachelle H. Crosbie. „Utrophin to the rescue“. Nature 384, Nr. 6607 (November 1996): 308–9. http://dx.doi.org/10.1038/384308a0.

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Tanihata, Jun, Naoki Suzuki, Yuko Miyagoe-Suzuki, Kazuhiko Imaizumi und Shin'ichi Takeda. „Downstream utrophin enhancer is required for expression of utrophin in skeletal muscle“. Journal of Gene Medicine 10, Nr. 6 (2008): 702–13. http://dx.doi.org/10.1002/jgm.1190.

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EBIHARA, SATORU, GHIABE-HENRI GUIBINGA, RENALD GILBERT, JOSEPHINE NALBANTOGLU, BERNARD MASSIE, GEORGE KARPATI und BASIL J. PETROF. „Differential effects of dystrophin and utrophin gene transfer in immunocompetent muscular dystrophy (mdx) mice“. Physiological Genomics 3, Nr. 3 (08.09.2000): 133–44. http://dx.doi.org/10.1152/physiolgenomics.2000.3.3.133.

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Ebihara, Satoru, Ghiabe-Henri Guibinga, Renald Gilbert, Josephine Nalbantoglu, Bernard Massie, George Karpati, and Basil J. Petrof. Differential effects of dystrophin and utrophin gene transfer in immunocompetent muscular dystrophy (mdx) mice. Physiol Genomics 3: 133–144, 2000.—Duchenne muscular dystrophy (DMD) is a fatal disease caused by defects in the gene encoding dystrophin. Dystrophin is a cytoskeletal protein, which together with its associated protein complex, helps to protect the sarcolemma from mechanical stresses associated with muscle contraction. Gene therapy efforts aimed at supplying a normal dystrophin gene to DMD muscles could be hampered by host immune system recognition of dystrophin as a “foreign” protein. In contrast, a closely related protein called utrophin is not foreign to DMD patients and is able to compensate for dystrophin deficiency when overexpressed throughout development in transgenic mice. However, the issue of which of the two candidate molecules is superior for DMD therapy has remained an open question. In this study, dystrophin and utrophin gene transfer effects on dystrophic muscle function were directly compared in the murine (mdx) model of DMD using E1/E3-deleted adenovirus vectors containing either a dystrophin (AdV-Dys) or a utrophin (AdV-Utr) transgene. In immunologically immature neonatal animals, AdV-Dys and AdV-Utr improved tibialis anterior muscle histopathology, force-generating capacity, and the ability to resist injury caused by high-stress contractions to an equivalent degree. By contrast, only AdV-Utr was able to achieve significant improvement in force generation and the ability to resist stress-induced injury in the soleus muscle of immunocompetent mature mdx animals. In addition, in mature mdx mice, there was significantly greater transgene persistence and reduced inflammation with utrophin compared to dystrophin gene transfer. We conclude that dystrophin and utrophin are largely equivalent in their intrinsic abilities to prevent the development of muscle necrosis and weakness when expressed in neonatal mdx animals with an immature immune system. However, because immunity against dystrophin places an important limitation on the efficacy of dystrophin gene replacement in an immunocompetent mature host, the use of utrophin as an alternative to dystrophin gene transfer in this setting appears to offer a significant therapeutic advantage.

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Banks, Glen B., Jeffrey S. Chamberlain und Guy L. Odom. „Microutrophin expression in dystrophic mice displays myofiber type differences in therapeutic effects“. PLOS Genetics 16, Nr. 11 (11.11.2020): e1009179. http://dx.doi.org/10.1371/journal.pgen.1009179.

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Gene therapy approaches for DMD using recombinant adeno-associated viral (rAAV) vectors to deliver miniaturized (or micro) dystrophin genes to striated muscles have shown significant progress. However, concerns remain about the potential for immune responses against dystrophin in some patients. Utrophin, a developmental paralogue of dystrophin, may provide a viable treatment option. Here we examine the functional capacity of an rAAV-mediated microutrophin (μUtrn) therapy in the mdx4cv mouse model of DMD. We found that rAAV-μUtrn led to improvement in dystrophic histopathology & mostly restored the architecture of the neuromuscular and myotendinous junctions. Physiological studies of tibialis anterior muscles indicated peak force maintenance, with partial improvement of specific force. A fundamental question for μUtrn therapeutics is not only can it replace critical functions of dystrophin, but whether full-length utrophin impacts the therapeutic efficacy of the smaller, highly expressed μUtrn. As such, we found that μUtrn significantly reduced the spacing of the costameric lattice relative to full-length utrophin. Further, immunostaining suggested the improvement in dystrophic pathophysiology was largely influenced by favored correction of fast 2b fibers. However, unlike μUtrn, μdystrophin (μDys) expression did not show this fiber type preference. Interestingly, μUtrn was better able to protect 2a and 2d fibers in mdx:utrn-/- mice than in mdx4cv mice where the endogenous full-length utrophin was most prevalent. Altogether, these data are consistent with the role of steric hindrance between full-length utrophin & μUtrn within the sarcolemma. Understanding the stoichiometry of this effect may be important for predicting clinical efficacy.

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Jimenez-Mallebrera, Cecilia, Kay Davies, Wendy Putt und Yvonne H. Edwards. „A study of short utrophin isoforms in mice deficient for full-length utrophin“. Mammalian Genome 14, Nr. 1 (01.01.2003): 47–60. http://dx.doi.org/10.1007/s00335-002-3044-z.

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Rafael, Jill A., Jonathon M. Tinsley, Allyson C. Potter, Anne E. Deconinck und Kay E. Davies. „Skeletal muscle-specific expression of a utrophin transgene rescues utrophin-dystrophin deficient mice“. Nature Genetics 19, Nr. 1 (Mai 1998): 79–82. http://dx.doi.org/10.1038/ng0598-79.

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Dove, Alan W. „Utrophin gets a new look“. Journal of Cell Biology 157, Nr. 2 (15.04.2002): 194. http://dx.doi.org/10.1083/jcb1572iti5.

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Sewry, C. A., K. J. Nowak, J. T. Ehmsen und K. E. Davies. „A and B utrophin in human muscle and sarcolemmal A-utrophin associated with tumours“. Neuromuscular Disorders 15, Nr. 11 (November 2005): 779–85. http://dx.doi.org/10.1016/j.nmd.2005.08.002.

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Costantini, Jennifer L., Samuel M. S. Cheung, Sen Hou, Hongzhao Li, Sam K. Kung, James B. Johnston, John A. Wilkins, Spencer B. Gibson und Aaron J. Marshall. „TAPP2 links phosphoinositide 3-kinase signaling to B-cell adhesion through interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting complex in B-cell leukemia“. Blood 114, Nr. 21 (19.11.2009): 4703–12. http://dx.doi.org/10.1182/blood-2009-03-213058.

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Abstract Tandem pleckstrin homology domain proteins (TAPPs) are recruited to the plasma membrane via binding to phosphoinositides produced by phosphoinositide 3-kinases (PI3Ks). Whereas PI3Ks are critical for B-cell activation, the functions of TAPP proteins in B cells are unknown. We have identified 40 potential interaction partners of TAPP2 in B cells, including proteins involved in cytoskeletal rearrangement, signal transduction and endocytic trafficking. The association of TAPP2 with the cytoskeletal proteins utrophin and syntrophin was confirmed by Western blotting. We found that TAPP2, syntrophin, and utrophin are coexpressed in normal human B cells and B-chronic lymphocytic leukemia (B-CLL) cells. TAPP2 and syntrophin expression in B-CLL was variable from patient to patient, with significantly higher expression in the more aggressive disease subset identified by zeta-chain–associated protein kinase of 70 kDa (ZAP70) expression and unmutated immunoglobulin heavy chain (IgH) genes. We examined whether TAPP can regulate cell adhesion, a known function of utrophin/syntrophin in other cell types. Expression of membrane-targeted TAPP2 enhanced B-cell adhesion to fibronectin and laminin, whereas PH domain–mutant TAPP2 inhibited adhesion. siRNA knockdown of TAPP2 or utrophin, or treatment with PI3K inhibitors, significantly inhibited adhesion. These findings identify TAPP2 as a novel link between PI3K signaling and the cytoskeleton with potential relevance for leukemia progression.

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Zuellig, Richard A., Beat C. Bornhauser, Ralf Amstutz, Bruno Constantin und Marcus C. Schaub. „Tissue Expression and Actin Binding of a Novel N-Terminal Utrophin Isoform“. Journal of Biomedicine and Biotechnology 2011 (2011): 1–18. http://dx.doi.org/10.1155/2011/904547.

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Utrophin and dystrophin present two large proteins that link the intracellular actin cytoskeleton to the extracellular matrix via the C-terminal-associated protein complex. Here we describe a novel short N-terminal isoform of utrophin and its protein product in various rat tissues (N-utro, 62 kDa, amino acids 1–539, comprising the actin-binding domain plus the first two spectrin repeats). Using different N-terminal recombinant utrophin fragments, we show that actin binding exhibits pronounced negative cooperativity (affinity constantsK1=∼5×106andK2=∼1×105 M-1) and is Ca2+-insensitive. Expression of the different fragments in COS7 cells and in myotubes indicates that the actin-binding domain alone binds exlusively to actin filaments. The recombinant N-utro analogue binds in vitro to actin and in the cells associates to the membranes. The results indicate that N-utro may be responsible for the anchoring of the cortical actin cytoskeleton to the membranes in muscle and other tissues.

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Nawrotzki, R., N. Y. Loh, M. A. Ruegg, K. E. Davies und D. J. Blake. „Characterisation of alpha-dystrobrevin in muscle“. Journal of Cell Science 111, Nr. 17 (01.09.1998): 2595–605. http://dx.doi.org/10.1242/jcs.111.17.2595.

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Dystrophin-related and associated proteins are important for the formation and maintenance of the mammalian neuromuscular junction. Initial studies in the electric organ of Torpedo californica showed that the dystrophin-related protein dystrobrevin (87K) co-purifies with the acetylcholine receptors and other postsynaptic proteins. Dystrobrevin is also a major phosphotyrosine-containing protein in the postsynaptic membrane. Since inhibitors of tyrosine protein phosphorylation block acetylcholine receptor clustering in cultured muscle cells, we examined the role of alpha-dystrobrevin during synapse formation and in response to agrin. Using specific antibodies, we show that C2 myoblasts and early myotubes only produce alpha-dystrobrevin-1, the mammalian orthologue of Torpedo dystrobrevin, whereas mature skeletal muscle expresses three distinct alpha-dystrobrevin isoforms. In myotubes, alpha-dystrobrevin-1 is found on the cell surface and also in acetylcholine receptor-rich domains. Following agrin stimulation, alpha-dystrobrevin-1 becomes re-localised beneath the cell surface into macroclusters that contain acetylcholine receptors and another dystrophin-related protein, utrophin. This redistribution is not associated with tyrosine phosphorylation of alpha-dystrobrevin-1 by agrin. Furthermore, we show that alpha-dystrobrevin-1 is associated with both utrophin in C2 cells and dystrophin in mature skeletal muscle. Thus alpha-dystrobrevin-1 is a component of two protein complexes in muscle, one with utrophin at the neuromuscular junction and the other with dystrophin at the sarcolemma. These results indicate that alpha-dystrobrevin-1 is not involved in the phosphorylation-dependent, early stages of receptor clustering, but rather in the stabilisation and maturation of clusters, possibly via an interaction with utrophin.

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Avila-Polo, R., E. Rivas, M. Cabrera-Serrano, P. Carbonell, I. Rojas-Marcos, Y. Morgado, E. Servian, M. Madruga, C. Marquez und C. Paradas. „Utrophin immunohistochemical expression in neuromuscular disorders“. Neuromuscular Disorders 26 (Oktober 2016): S206. http://dx.doi.org/10.1016/j.nmd.2016.06.434.

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Nelson, Roxanne. „Utrophin therapy for Duchenne muscular dystrophy?“ Lancet Neurology 3, Nr. 11 (November 2004): 637. http://dx.doi.org/10.1016/s1474-4422(04)00891-9.

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Belanto, J. J., T. L. Mader, M. D. Eckhoff, D. M. Strandjord, G. B. Banks, M. K. Gardner, D. A. Lowe und J. M. Ervasti. „Microtubule binding distinguishes dystrophin from utrophin“. Proceedings of the National Academy of Sciences 111, Nr. 15 (31.03.2014): 5723–28. http://dx.doi.org/10.1073/pnas.1323842111.

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Karpati, George. „Utrophin muscles in on the action“. Nature Medicine 3, Nr. 1 (Januar 1997): 22–23. http://dx.doi.org/10.1038/nm0197-22.

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Basu, Utpal, Olga Lozynska, Catherine Moorwood, Gopal Patel, Steve D. Wilton und Tejvir S. Khurana. „Translational Regulation of Utrophin by miRNAs“. PLoS ONE 6, Nr. 12 (27.12.2011): e29376. http://dx.doi.org/10.1371/journal.pone.0029376.

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Santas, Amy J., Danielle L. Lavery, Chelsea F. Popowski, April Y. Hung, Ryan E. Hunt, Mary K. Richardson und Kristin M. Braun. „Utrophin Expression is Prevalent in Epidermis“. BIOS 81, Nr. 3 (September 2010): 67–75. http://dx.doi.org/10.1893/011.081.0301.

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Winder, S. J., T. J. Gibson und J. Kendrick-Jones. „Dystrophin and utrophin: the missing links!“ FEBS Letters 369, Nr. 1 (01.08.1995): 27–33. http://dx.doi.org/10.1016/0014-5793(95)00398-s.

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Rigoletto, C., A. Prelle, P. Ciscato, M. Moggio, G. Comi, F. Fortunato und G. Scarlato. „Utrophin expression during human fetal development“. International Journal of Developmental Neuroscience 13, Nr. 6 (Oktober 1995): 585–93. http://dx.doi.org/10.1016/0736-5748(95)00039-j.

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Tinsley, Jonathon M., und Kay E. Davies. „Utrophin: A potential replacement for dystrophin?“ Neuromuscular Disorders 3, Nr. 5-6 (Januar 1993): 537–39. http://dx.doi.org/10.1016/0960-8966(93)90111-v.

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Winder, Steven J., Lance Hemmings, Sarah J. Bolton, Sutherland K. Maciver, Jon M. Tinsley, Kay E. Davies, David R. Critchley und John Kendrick-Jones. „Calmodulin regulation of utrophin actin binding“. Biochemical Society Transactions 23, Nr. 3 (01.08.1995): 397S. http://dx.doi.org/10.1042/bst023397s.

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Ramachandran, Jayalakshmi, Joel S. Schneider, Pierre-Antoine Crassous, Ruifang Zheng, James P. Gonzalez, Lai-Hua Xie, Annie Beuve, Diego Fraidenraich und R. Daniel Peluffo. „Nitric oxide signalling pathway in Duchenne muscular dystrophy mice: up-regulation of L-arginine transporters“. Biochemical Journal 449, Nr. 1 (07.12.2012): 133–42. http://dx.doi.org/10.1042/bj20120787.

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DMD (Duchenne muscular dystrophy) is an incurable rapidly worsening neuromuscular degenerative disease caused by the absence of dystrophin. In skeletal muscle a lack of dystrophin disrupts the recruitment of neuronal NOS (nitric oxide synthase) to the sarcolemma thus affecting NO (nitric oxide) production. Utrophin is a dystrophin homologue, the expression of which is greatly up-regulated in the sarcolemma of dystrophin-negative fibres from mdx mice, a mouse model of DMD. Although cardiomyopathy is an important cause of death, little is known about the NO signalling pathway in the cardiac muscle of DMD patients. Thus we used cardiomyocytes and hearts from two month-old mdx and mdx:utrophin−/− (double knockout) mice (mdx:utr) to study key steps in NO signalling: L-arginine transporters, NOS and sGC (soluble guanylyl cyclase). nNOS did not co-localize with dystrophin or utrophin to the cardiomyocyte membrane. Despite this nNOS activity was markedly decreased in both mdx and mdx:utr mice, whereas nNOS expression was only decreased in mdx:utr mouse hearts, suggesting that utrophin up-regulation in cardiomyocytes maintains nNOS levels, but not function. sGC protein levels and activity remained at control levels. Unexpectedly, L-arginine transporter expression and function were significantly increased, suggesting a novel biochemical compensatory mechanism of the NO pathway and a potential entry site for therapeutics.

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Sekulic-Jablanovic, Marijana, Nina D. Ullrich, David Goldblum, Anja Palmowski-Wolfe, Francesco Zorzato und Susan Treves. „Functional characterization of orbicularis oculi and extraocular muscles“. Journal of General Physiology 147, Nr. 5 (11.04.2016): 395–406. http://dx.doi.org/10.1085/jgp.201511542.

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The orbicularis oculi are the sphincter muscles of the eyelids and are involved in modulating facial expression. They differ from both limb and extraocular muscles (EOMs) in their histology and biochemistry. Weakness of the orbicularis oculi muscles is a feature of neuromuscular disorders affecting the neuromuscular junction, and weakness of facial muscles and ptosis have also been described in patients with mutations in the ryanodine receptor gene. Here, we investigate human orbicularis oculi muscles and find that they are functionally more similar to quadriceps than to EOMs in terms of excitation–contraction coupling components. In particular, they do not express the cardiac isoform of the dihydropyridine receptor, which we find to be highly expressed in EOMs where it is likely responsible for the large depolarization-induced calcium influx. We further show that human orbicularis oculi and EOMs express high levels of utrophin and low levels of dystrophin, whereas quadriceps express dystrophin and low levels of utrophin. The results of this study highlight the notion that myotubes obtained by explanting satellite cells from different muscles are not functionally identical and retain the physiological characteristics of their muscle of origin. Furthermore, our results indicate that sparing of facial and EOMs in patients with Duchenne muscular dystrophy is the result of the higher levels of utrophin expression.

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Kachinsky, Amy M., Stanley C. Froehner und Sharon L. Milgram. „A PDZ-containing Scaffold Related to the Dystrophin Complex at the Basolateral Membrane of Epithelial Cells“. Journal of Cell Biology 145, Nr. 2 (19.04.1999): 391–402. http://dx.doi.org/10.1083/jcb.145.2.391.

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Membrane scaffolding complexes are key features of many cell types, serving as specialized links between the extracellular matrix and the actin cytoskeleton. An important scaffold in skeletal muscle is the dystrophin-associated protein complex. One of the proteins bound directly to dystrophin is syntrophin, a modular protein comprised entirely of interaction motifs, including PDZ (protein domain named for PSD-95, discs large, ZO-1) and pleckstrin homology (PH) domains. In skeletal muscle, the syntrophin PDZ domain recruits sodium channels and signaling molecules, such as neuronal nitric oxide synthase, to the dystrophin complex. In epithelia, we identified a variation of the dystrophin complex, in which syntrophin, and the dystrophin homologues, utrophin and dystrobrevin, are restricted to the basolateral membrane. We used exogenously expressed green fluorescent protein (GFP)-tagged fusion proteins to determine which domains of syntrophin are responsible for its polarized localization. GFP-tagged full-length syntrophin targeted to the basolateral membrane, but individual domains remained in the cytoplasm. In contrast, the second PH domain tandemly linked to a highly conserved, COOH-terminal region was sufficient for basolateral membrane targeting and association with utrophin. The results suggest an interaction between syntrophin and utrophin that leaves the PDZ domain of syntrophin available to recruit additional proteins to the epithelial basolateral membrane. The assembly of multiprotein signaling complexes at sites of membrane specialization may be a widespread function of dystrophin-related protein complexes.

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