title: Transcriptional activation of the utrophin promoter B by a constitutively active Ets-transcription factor.
abstract: Duchenne muscular dystrophy is an X-linked genetic disease caused by the absence of functional dystrophin. Pharmacological upregulation of utrophin, the autosomal homologue of dystrophin, offers a potential therapeutic approach to treat Duchenne patients. Full-length utrophin mRNA is transcribed from two alternative promoters, called A and B. In contrast to the utrophin promoter A, little is known about the factors regulating the activity of the utrophin promoter B. Computer analysis of this second promoter revealed the presence of several conserved binding motives for Ets-transcription factors. Using electrotransfer of cDNA into mouse muscles, we demonstrate that a genetically modified beta-subunit of the Ets-transcription factor GA-binding protein potently activates a utrophin promoter B reporter construct in innervated muscle fibers in vivo. These results make the GA-binding protein and the signaling cascade regulating its activity in muscle cells, potential targets for the pharmacological modulation of utrophin expression in Duchenne patients.
authors.affiliation: MyoContract Ltd, Hammerstrasse 25, CH-4410, Liestal, Switzerland. alexandre.briguet@myocontract.com
authors.forename: Alexandre
authors.initials: A
authors.lastname: Briguet
authors.forename: Dorothee
authors.initials: D
authors.lastname: Bleckmann
authors.forename: Mickaël
authors.initials: M
authors.lastname: Bettan
authors.forename: Nicolas
authors.initials: N
authors.lastname: Mermod
authors.forename: Thomas
authors.initials: T
authors.lastname: Meier
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D016466:CHO Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003402:Creatine Kinase / Q000378:metabolism; D052283:Creatine Kinase, MM Form; D006224:Cricetinae; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000145:classification / Q000235:genetics / Q000502:physiology*; D051268:GA-Binding Protein Transcription Factor; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000378:metabolism; D008565:Membrane Proteins / Q000145:classification / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D032446:Myoblasts / Q000378:metabolism*; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D020890:Neuregulin-1 / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D021122:Protein Subunits / Q000145:classification / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000145:classification / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection / Q000379:methods; D015854:Up-Regulation; D049411:Utrophin; D028901:alpha Karyopherins / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051268:GA-Binding Protein Transcription Factor; C495658:Gabpb1 protein, mouse; D007527:Isoenzymes; D008565:Membrane Proteins; D019006:Neural Cell Adhesion Molecules; D020890:Neuregulin-1; D021122:Protein Subunits; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D014157:Transcription Factors; C483600:Utrn protein, mouse; D049411:Utrophin; D028901:alpha Karyopherins; D003402:Creatine Kinase; D052283:Creatine Kinase, MM Form