Activation of utrophin promoter by heregulin via the ets-related transcription factor complex GA-binding protein alpha/beta

Utrophin/dystrophin-related protein is the autosomal homologue of the chrom osome X-encoded dystrophin protein. In adult skeletal muscle, utrophin is h ighly enriched at the neuromuscular junction. However, the molecular mechan isms underlying regulation of utrophin gene expression are yet to be define d. Here we demonstrate that the growth factor heregulin increases de novo u trophin transcription in muscle cell cultures. Using mutant reporter constr ucts of the utrophin promoter, we define the N-box region of the promoter a s critical for heregulin-mediated activation. Using this region of the utro phin promoter for DNA affinity purification, immunoblots, in vitro kinase a ssays, electrophoretic mobility shift assays, and in vitro expression in cu ltured muscle cells, we demonstrate that ets-related GA-binding protein alp ha/beta transcription factors are activators of the utrophin promoter. Take n together, these results suggest that the GA-binding protein alpha/beta co mplex of transcription factors binds and activates the utrophin promoter in response to heregulin-activated extracellular signal-regulated kinase in m uscle cell cultures. These findings suggest methods for achieving utrophin up-regulation in Duchenne's muscular dystrophy as well as mechanisms by whi ch neurite-derived growth factors such as heregulin may influence the regul ation of utrophin gene expression and subsequent enrichment at the neuromus cular junction of skeletal muscle.