title: FGF inactivates myogenic helix-loop-helix proteins through phosphorylation of a conserved protein kinase C site in their DNA-binding domains.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: J
authors.initials: J
authors.lastname: Zhou
authors.forename: G
authors.initials: G
authors.lastname: James
authors.forename: R
authors.initials: R
authors.lastname: Heller-Harrison
authors.forename: M P
authors.initials: MP
authors.lastname: Czech
authors.forename: E N
authors.initials: EN
authors.lastname: Olson
mesh_terms: 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*
chemical_list: D009124:Muscle Proteins; D018008:Myogenin; D015534:Trans-Activators; D005346:Fibroblast Growth Factors; D011493:Protein Kinase C