Critical activities of Rac1 and Cdc42Hs in skeletal myogenesis: antagonistic effects of JNK and p38 pathways.
The Rho family of GTP-binding proteins plays a critical role in a variety of cellular processes, including cytoskeletal reorganization and activation of kinases such as p38 and C-jun N-terminal kinase (JNK) MAPKs. We report here that dominant negative forms of Rac1 and Cdc42Hs inhibit the expression of the muscle-specific genes myogenin, troponin T, and myosin heavy chain in L6 and C2 myoblasts. Such inhibition correlates with decreased p38 activity. Active RhoA, RhoG, Rac1, and Cdc42Hs also prevent myoblast-to-myotube transition but affect distinct stages: RhoG, Rac1, and Cdc42Hs inhibit the expression of all muscle-specific genes analyzed, whereas active RhoA potentiates their expression but prevents the myoblast fusion process. We further show by two different approaches that the inhibitory effects of active Rac1 and Cdc42Hs are independent of their morphogenic activities. Rather, myogenesis inhibition is mediated by the JNK pathway, which also leads to a cytoplasmic redistribution of Myf5. We propose that although Rho proteins are required for the commitment of myogenesis, they differentially influence this process, positively for RhoA and Rac1/Cdc42Hs through the activation of the SRF and p38 pathways, respectively, and negatively for Rac1/Cdc42Hs through the activation of the JNK pathway.
Centre de Recherche de Biochimie Macromoléculaire, Centre National de la Recherche Scientifique Unité Propre de Recherche, Montpellier, France.
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Meriane
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Roux
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Primig
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Fort
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Gauthier-Rouvière
D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051787:Myogenic Regulatory Factor 5; D018008:Myogenin / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D051381:Rats; D015534:Trans-Activators; D014162:Transfection; D014336:Troponin / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000502:physiology
D004268:DNA-Binding Proteins; D009124:Muscle Proteins; C497418:Myf5 protein, mouse; C503801:Myog protein, mouse; C503803:Myog protein, rat; D051787:Myogenic Regulatory Factor 5; D018008:Myogenin; D015534:Trans-Activators; D014336:Troponin; D000841:Anisomycin; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018995:Myosin Heavy Chains; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins