FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains.
Myogenin belongs to a family of myogenic helix-loop-helix (HLH) proteins that activate muscle transcription through binding to a conserved DNA sequence associated with numerous muscle-specific genes. Fibroblast growth factor (FGF) inhibits myogenesis by inactivating myogenic HLH proteins. We show that activated protein kinase C (PKC) can substitute for FGF and inhibit transcriptional activity of myogenic HLH proteins. In transfected cells, FGF induces phosphorylation of a conserved site in the DNA-binding domain of myogenin. This site is phosphorylated by PKC in vivo and in vitro and mediates repression of the myogenic program through a loss in DNA binding activity. A myogenin mutant lacking the PKC phosphorylation site is not repressed by FGF, confirming this site as a molecular target for FGF-dependent repression of muscle transcription. These results establish a direct link between the signal transduction pathways that inhibit myogenesis and the transcription factors directly activating muscle-specific genes.
Li
L
L
Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Zhou
J
J
James
G
G
Heller-Harrison
R
R
Czech
M P
MP
Olson
E N
EN
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000187:drug effects*; D018008:Myogenin; D010766:Phosphorylation; D011493:Protein Kinase C / Q000494:pharmacology*; D015398:Signal Transduction; D015534:Trans-Activators; D014158:Transcription, Genetic / Q000187:drug effects*
D009124:Muscle Proteins; D018008:Myogenin; D015534:Trans-Activators; D005346:Fibroblast Growth Factors; D011493:Protein Kinase C