DIFFERENTIAL REGULATION OF PRIMARY RESPONSE GENE-EXPRESSION IN SKELETAL-MUSCLE CELLS THROUGH MULTIPLE SIGNAL-TRANSDUCTION PATHWAYS

One of the earliest cellular responses to growth factors is the rapid induction of primary response genes. One group of such genes was origi nally isolated as tetradecanoyl phorbol acetate (TPA) inducible sequen ces (TIS genes) from mouse 3T3 cells. Proteins encoded by the TIS gene s include two transcription factors: TIS8 (also known as egr1/NGFIA/zi f268) and TIS1 (also known as NGFIB/nur77/N10). We have examined the i nducibility of these two genes in a skeletal muscle cell line in respo nse to agents that have been reported to block muscle differentiation. We report here that basic fibroblast growth factor (bFGF) induced the expression of both TIS1 and TIS8 in mouse C2C12cells. Both genes were also inducible by TPA while forskolin which activates the cAMP-depend ent pathway induced TIS1 but not TIS8. Down-regulation of protein kina se C (PKC) activity by TPA pretreatment repressed the bFGF induction o f TIS1 but had little effect on the bFGF-stimulated expression of TIS8 . Moreover, while both TPA and bFGF stimulated the hyperphosphorylatio n of c-RAF and the activity of MAP kinase, TPA pretreatment failed to block RAF phosphorylation or the stimulation of MAP kinase activity by bFGF. Induction of the two TIS genes in skeletal myoblasts therefore appeared to be dependent to different extents on the activation of pro tein kinase A (PKA), PKC and MAP kinase.