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TGF-β inhibits muscle differentiation through functional repression of myogenic transcription factors by Smad3
Open accessAbstract
Transforming growth factor-β (TGF-β) 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-β 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-β. 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-β, through Smad3-mediated transcriptional repression, inhibits myogenic differentiation.
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“Myostatin is a ligand of the TGF-β pathway in skeletal muscle and a well-known negative regulator of muscle mass, as it inhibits satellite cells’ proliferation and differentiation [174].”
From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [174]
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Self-citation
Metadata
- Authors
- Liu, D., Black, B. L., & Derynck, R.
- Affiliations
- University of California, San Francisco (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2001-11-15
- Volume
- 15
- Issue
- 22
- Pages
- 2950-2966
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC312830
- OpenAlex
- W2116961946
- Cited by
- 399
- References
- 80
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 22 · 2023: 16 · 2022: 23 · 2021: 16 · 2020: 11 · 2019: 26 · 2018: 19 · 2017: 13 · 2016: 19 · 2015: 13 · 2014: 9 · 2013: 27 · 2012: 14
- Type
- posted content
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA063101, R01-CA63101)
- National Institute of Dental and Craniofacial Research (P60DE013058, P60 DE-13058)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- TGF-beta, Smad3, Smad2, skeletal muscle differentiation, myogenesis, MyoD, E-box, bHLH transcription factors, E12, E47, E protein, transcriptional repression, heterodimerization, C2C12 myoblasts, C3H10T1/2 cells
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Cells, Cultured, DNA-Binding Proteins, Glutathione Transferase, Luciferases, Microscopy, Fluorescence, Plasmids, Protein Binding, Recombinant Fusion Proteins, Retroviridae, Transcription, Genetic, Transfection, Blotting, Western, Signal Transduction, Trans-Activators, Transforming Growth Factor beta, Protein Structure, Tertiary, MyoD Protein, Muscle, Skeletal, Dimerization, COS Cells, Mice, Smad3 Protein
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