Identification of intracellular signaling pathways that induce myotonic dystrophy protein kinase expression during myogenesis.
Myotonic dystrophy (DM) is the most common inherited adult neuromuscular disorder. DM is caused by a CTG expansion in the 3'-untranslated region of a protein kinase gene (DMPK). Decreased DMPK protein levels may contribute to the pathology of DM, as revealed by gene target studies. However, the postnatal regulation of DMPK expression and its pathophysiological role remain undefined. We studied the regulation of DMPK protein and mRNA expression during myogenesis in rat L6E9 myoblasts, mouse C2C12 myoblasts, and 10T1/2 fibroblasts stably expressing the myogenic transcription factor MyoD (10T1/2-MyoD). We detected DMPK as an 80-kDa protein mainly localized to the cytosolic fraction of skeletal muscle cells. DMPK expression and protein kinase activity were enhanced in IGF-II-differentiated cells. In L6E9 and C2C12 cells, DMPK expression was regulated through the same signaling pathways (i.e. phosphatidylinositol 3-kinase, nuclear factor-kappaB, nitric oxide synthase, and p38 mitogen-activated protein kinase) that had been described as being crucial for the myogenesis induced by either low serum or IGF-II. However, in 10T1/2-MyoD cells, p38 MAPK inhibition blocked cell fusion and caveolin-3 expression without affecting DMPK up-regulation. These results suggest that although DMPK is induced during myogenesis, its expression cannot be totally associated with the development of a fully differentiated phenotype.
Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, E-08028 Barcelona, Spain.
Marta
M
Carrasco
Judith
J
Canicio
Manuel
M
Palacín
Antonio
A
Zorzano
Perla
P
Kaliman
D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D007335:Insulin-Like Growth Factor II / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D018482:Muscle, Skeletal / Q000196:embryology* / Q000201:enzymology*; D009223:Myotonic Dystrophy / Q000209:etiology*; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases
C585516:DMPK protein, mouse; D007335:Insulin-Like Growth Factor II; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases