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Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by the absence of dystrophin. Utrophin is the autosomal homolog of dystrophin and capable of compensating for the absence of dystrophin, when overexpressed. In skeletal muscle, utrophin plays an important role in the formation of neuromuscular junctions. This selective enrichment occurs, in part by transcriptional regulation of the utrophin gene at the sub-synaptic nuclei in muscle. Utrophin's complex transcriptional regulation is not yet fully understood, however, GABP alpha / beta has recently been shown to bind the N box and activate the utrophin promoter in response to heregulin. In this study, we show that the transcription factor Sp1 binds and activates the utrophin promoter in Drosophila S2 cells as well as define a Sp1 response element. We demonstrate that heregulin treatment of cultured muscle cells activates the ERK pathway and phosphorylates serine residue(s) in the consensus ERK recognition site of Sp1. Finally, Sp1 is shown to functionally cooperate with GABP alpha / beta and cause a 58-fold increase of de novo utrophin promoter transcription. Taken together, these findings help define mechanisms used for transcriptional regulation of utrophin expression as well as identify new targets for achieving potentially therapeutic upregulation of utrophin in DMD.

Type

Journal article

Journal

J Neurol Sci

Publication Date

15/05/2002

Volume

197

Pages

27 - 35

Keywords

Animals, Binding Sites, Cells, Cultured, Cytoskeletal Proteins, DNA-Binding Proteins, Drosophila, Electrophoretic Mobility Shift Assay, GA-Binding Protein Transcription Factor, Gene Expression Regulation, Humans, Immunoblotting, Membrane Proteins, Muscle Fibers, Skeletal, Muscular Dystrophy, Duchenne, Mutagenesis, Site-Directed, Oncogene Proteins, Precipitin Tests, Promoter Regions, Genetic, Proto-Oncogene Proteins c-ets, Sp1 Transcription Factor, Transcription Factors, Utrophin