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Vol. 10, Issue 6, 2075-2086, June 1999
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*Department of Clinical Biochemistry, University of Copenhagen
Medical School, The Glostrup Hospital, Glostrup DK 2600, Denmark;
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 that
ets-related GA-binding protein Division of Hematology, Brown University Department of
Medicine, and Division of Hematology/Oncology, The Miriam Hospital,
Providence, Rhode Island 02906; and §Department of
Neurobiology, Harvard Medical School, Boston, Massachusetts 02115
/
transcription factors are activators of the utrophin promoter. Taken
together, these results suggest that the GA-binding protein /
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.
Corresponding author. E-mail address:
tsk{at}dcb-glostrup.dk.
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