Ets-2 repressor factor silences extrasynaptic utrophin by N-box-mediated repression in skeletal muscle


Perkins K. J. , Basu U., Budak M. T. , Ketterer C., Baby S. M. , Lozynska O., ...Daha Fazla

MOLECULAR BIOLOGY OF THE CELL, cilt.18, sa.8, ss.2864-2872, 2007 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Cilt numarası: 18 Konu: 8
  • Basım Tarihi: 2007
  • Doi Numarası: 10.1091/mbc.e06-12-1069
  • Dergi Adı: MOLECULAR BIOLOGY OF THE CELL
  • Sayfa Sayıları: ss.2864-2872

Özet

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 GABP alpha/beta 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.