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PMID:11711431
| Citation |
Liu, D, Black, BL and Derynck, R (2001) TGF-beta inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3. Genes Dev. 15:2950-66 |
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| Abstract |
Transforming growth factor-beta (TGF-beta) is a potent inhibitor of skeletal muscle differentiation, but the molecular mechanism and signaling events that lead to this inhibition are poorly characterized. Here we show that the TGF-beta intracellular effector Smad3, but not Smad2, mediates the inhibition of myogenic differentiation in MyoD-expressing C3H10T1/2 cells and C2C12 myoblasts by repressing the activity of the MyoD family of transcriptional factors. The Smad3-mediated repression was directed at the E-box sequence motif within muscle gene enhancers and the bHLH region of MyoD, the domain required for its association with E-protein partners such as E12 and E47. The repression could be overcome by supplying an excess of E12, and covalent tethering of E47 to MyoD rendered the E-box-dependent transcriptional activity refractory to the effects of Smad3 and TGF-beta. Smad3 physically interacted with the HLH domain of MyoD, and this interaction correlated with the ability of Smad3 to interfere with MyoD/E protein heterodimerization and binding of MyoD complexes to oligomerized E-box sites. Together, these results reveal a model for how TGF-beta, through Smad3-mediated transcriptional repression, inhibits myogenic differentiation. |
| Links |
PubMed PMC312830 Online version:10.1101/gad.925901 |
| Keywords |
Animals; Blotting, Western; COS Cells; Cell Differentiation; Cell Line; Cells, Cultured; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Dimerization; Glutathione Transferase/metabolism; Luciferases/metabolism; Mice; Microscopy, Fluorescence; Muscle, Skeletal/cytology; Muscle, Skeletal/metabolism; MyoD Protein/metabolism; Plasmids/metabolism; Protein Binding; Protein Structure, Tertiary; Recombinant Fusion Proteins/metabolism; Retroviridae/genetics; Signal Transduction; Smad3 Protein; Trans-Activators/genetics; Trans-Activators/metabolism; Transcription, Genetic; Transfection; Transforming Growth Factor beta/genetics; Transforming Growth Factor beta/metabolism |
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Significance
Annotations
| Gene product | Qualifier | GO ID | GO term name | Evidence Code | with/from | Aspect | Notes | Status |
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