Regulation of C2C12 myogenic terminal differentiation by MKK3/p38alpha pathway.
The signal transduction pathways connecting cell surface receptors to the activation of muscle-specific promoters and leading to myogenesis are still largely unknown. Recently, a contribution of the p38 mitogen-activated protein kinase (MAPK) pathway to this process was evoked through the use of pharmacological inhibitors. We used several mutants of the kinases composing this pathway to modulate the activity of the muscle-specific myosin light chain and myogenin promoters in C2C12 cells by transient transfections. In addition, we show for the first time, using a stable C2C12 cell line expressing a dominant-negative form of the p38 activator MAPK kinase (MKK)3, that a functional p38 MAPK pathway is indeed required for terminal muscle cell differentiation. The most obvious phenotype of this cell line, besides the inhibition of the activation of p38, is its inability to undergo terminal differentiation. This phenotype is accompanied by a drastic inhibition of cell cycle and myogenesis markers such as p21, p27, MyoD, and troponin T, as well as a profound disorganization of the cytoskeleton.
Cabane
Candice
C
Unité Mixte de Recherche Centre National de la Recherche Scientifique 6548, Laboratoire de Physiologie Cellulaire et Moléculaire, Faculté des Sciences, Université de Nice-Sophia Antipolis, France.
Englaro
Walter
W
Yeow
Karen
K
Ragno
Michel
M
Dérijard
Benoît
B
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048371:MAP Kinase Kinase 3; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology* / Q000201:enzymology*; D017570:MyoD Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000166:cytology / Q000201:enzymology*; D018008:Myogenin / Q000037:antagonists & inhibitors / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000187:drug effects / Q000378:metabolism; D018994:Myosin Light Chains / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D017570:MyoD Protein; C503801:Myog protein, mouse; D018008:Myogenin; D018994:Myosin Light Chains; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D048308:Mitogen-Activated Protein Kinase 14; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D048371:MAP Kinase Kinase 3; C482531:Map2k3 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D018995:Myosin Heavy Chains