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.
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.
Rousse
S
S
INSERM U515, Hôpital Saint Antoine, 75571 Paris Cedex 12, France.
Lallemand
F
F
Montarras
D
D
Pinset
C
C
Mazars
A
A
Prunier
C
C
Atfi
A
A
Dubois
C
C
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D002454:Cell Differentiation; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005799:Genes, Dominant; D007328:Insulin / Q000378:metabolism; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases; D008156:Luciferases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D020107:Troponin T / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D007328:Insulin; D018975:Insulin-Like Growth Factor Binding Protein 5; D012333:RNA, Messenger; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D020107:Troponin T; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases