REGULATION OF DISTINCT STAGES OF SKELETAL-MUSCLE DIFFERENTIATION BY MITOGEN-ACTIVATED PROTEIN-KINASES

The signal transduction pathway or pathways linking extracellular sign als to myogenesis are poorly defined. Upon mitogen withdrawal from C2C 12 myoblasts, the mitogen-activated protein kinase (MAPK) p42Erk2 is i nactivated concomitant with up-regulation of muscle-specific genes, Ov erexpression of MAPK phosphatase-1 (MKP-1) inhibited p42Erk2 activity and was sufficient to relieve the inhibitory effects of mitogens on mu scle-specific gene expression. Later during myogenesis, endogenous exp ression of MKP-1 decreased. MKP-1 overexpression during differentiatio n prevented myotube formation despite appropriate expression of myosin heavy chain, This indicates that muscle-specific gene expression is n ecessary but not sufficient to commit differentiated myocytes to myotu bes and suggests a function for tile MAPKs during the early and late s tages of skeletal muscle differentiation.