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TGF‐β‐activated Smad3 represses MEF2‐dependent transcription in myogenic differentiation
Author(s) -
Liu Dong,
Kang Jong Seok,
Derynck Rik
Publication year - 2004
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600179
Subject(s) - myod , myogenin , myogenesis , mef2 , transcription factor , microbiology and biotechnology , mef2c , biology , transforming growth factor beta , myocyte , signal transduction , gene , genetics , enhancer
Transforming growth factor β (TGF‐β) inhibits myogenesis and associated gene expression. We previously reported that the TGF‐β signaling effector Smad3 mediates this inhibition, by interfering with the assembly of myogenic bHLH transcription factor heterodimers on E‐box sequences in the regulatory regions of muscle‐specific genes. We now show that TGF‐β‐activated Smad3 suppresses the function of MEF2, a second class of essential myogenic factors. TGF‐β signaling through Smad3 represses myogenin expression independently of E‐boxes, and prevents a tethered MyoD‐E47 dimer to activate transcription indirectly through MEF2‐binding sites. In addition, Smad3 interacts with MEF2C, which requires its MADS domain, and disrupts its association with the SRC‐family coactivator GRIP‐1, thus diminishing the transcription activity of MEF2C. Consistent with this physical displacement, TGF‐β signaling blocks the GRIP‐1‐induced redistribution of MEF2C to discrete nuclear subdomains in 10T1/2 cells, and the recruitment of GRIP‐1 to the myogenin promoter in differentiating myoblasts. These findings indicate that the TGF‐β/Smad3 pathway targets two critical components of the myogenic transcription machinery to inhibit terminal differentiation.