Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle Proteins / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / genetics*
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Cells, Cultured
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Cyclin-Dependent Kinase Inhibitor p27
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MAP Kinase Kinase 3
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MAP Kinase Kinase Kinase 1*
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Mice
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Mitogen-Activated Protein Kinase 14
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Mitogen-Activated Protein Kinase Kinases / drug effects
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Mitogen-Activated Protein Kinases / drug effects
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism*
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Muscle Fibers, Skeletal / cytology
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / enzymology*
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Muscle Fibers, Skeletal / metabolism
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Muscle, Skeletal / cytology
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Muscle, Skeletal / embryology*
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Muscle, Skeletal / enzymology*
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MyoD Protein / antagonists & inhibitors
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MyoD Protein / metabolism
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Myoblasts, Skeletal / cytology
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Myoblasts, Skeletal / enzymology*
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Myogenin / antagonists & inhibitors
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Myogenin / metabolism
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Myosin Heavy Chains / drug effects
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Myosin Heavy Chains / metabolism
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Myosin Light Chains / antagonists & inhibitors
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Myosin Light Chains / metabolism
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / drug effects
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism*
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Tumor Suppressor Proteins / metabolism
Substances
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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MyoD Protein
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Myog protein, mouse
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Myogenin
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Myosin Light Chains
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 14
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinase 1
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Map3k1 protein, mouse
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MAP Kinase Kinase 3
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Map2k3 protein, mouse
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Mitogen-Activated Protein Kinase Kinases
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Myosin Heavy Chains