Transforming growth factor-beta inhibition of insulin-like growth factor-binding protein-5 synthesis in skeletal muscle cells involves a c-Jun N-terminal kinase-dependent pathway

J Biol Chem. 2001 Dec 14;276(50):46961-7. doi: 10.1074/jbc.M104440200. Epub 2001 Oct 11.

Abstract

Transforming growth factor-beta (TGF-beta) and insulin-like growth factors (IGFs) play critical roles in the control of myogenesis. Insulin-like growth factor-binding protein-5 (IGFBP-5), by regulating the bioavailability of IGFs, is involved in controlling IGF-dependent differentiation. We investigated the effects of TGF-beta on the IGFBP-5 production induced by IGFs in mouse myoblasts. TGF-beta leads to a decrease in IGFBP-5 synthesis at both transcript and protein levels, and blocked muscle differentiation. The Smad proteins and the c-Jun N-terminal kinase (JNK) have been shown to be involved in TGF-beta signaling pathways. We provide evidence that the JNK pathway, rather than Smad proteins, is involved in the response of muscle cells to TGF-beta. This factor failed to stimulate the GAL4-Smad 2/3 transcriptional activities of the constructs used to transfect myoblasts. Moreover, stable expression of the antagonistic Smad7 did not abolish the inhibitory effect of TGF-beta on IGFBP-5 production whereas expression of a dominant-negative version of MKK4, an upstream activator of JNK, did. We also showed, using a specific inhibitor, that the p38 mitogen-activated protein kinase (p38 MAPK) was not involved in the inhibition of IGFBP-5 production. Thus, TGF-beta-mediated IGFBP-5 inhibition is independent of Smads and requires activation of the JNK signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Northern
  • Cell Differentiation
  • Cells, Cultured
  • DNA-Binding Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • Genes, Dominant
  • Insulin / metabolism
  • Insulin-Like Growth Factor Binding Protein 5 / antagonists & inhibitors*
  • Insulin-Like Growth Factor Binding Protein 5 / biosynthesis
  • Insulin-Like Growth Factor Binding Protein 5 / metabolism*
  • JNK Mitogen-Activated Protein Kinases
  • Luciferases / metabolism
  • MAP Kinase Kinase 4*
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / genetics
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinases / metabolism*
  • Muscle, Skeletal / metabolism*
  • Mutation
  • Plasmids / metabolism
  • Protein Binding
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Smad2 Protein
  • Smad3 Protein
  • Smad7 Protein
  • Trans-Activators / metabolism
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Transforming Growth Factor beta / metabolism*
  • Troponin T / metabolism
  • p38 Mitogen-Activated Protein Kinases

Substances

  • DNA-Binding Proteins
  • Insulin
  • Insulin-Like Growth Factor Binding Protein 5
  • RNA, Messenger
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad7 Protein
  • Smad7 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Troponin T
  • Luciferases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Map2k4 protein, mouse
  • Mitogen-Activated Protein Kinase Kinases