Published online before print January 22, 2004, doi: 10.1161/01.RES.0000118599.25944.D5
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© 2004 American Heart Association, Inc.
Molecular Medicine |
Transforming Growth Factor-ß–Induced Inhibition of Myogenesis Is Mediated Through Smad Pathway and Is Modulated by Microtubule Dynamic Stability
From the Division of Cardiology, Department of Internal Medicine, Duke University Medical Center, Durham, NC 27710
Correspondence to Chunming Dong, Division of Cardiology, Duke University Medical Center, 406 Sands Building, Research Drive, Durham, NC 27710. E-mail dong0005{at}mc.duke.edu
The expression of muscle-specific genes associated with myogenesis is controlled by several myogenic transcription factors, including myogenin and MEF2D. Transforming growth factor-ß (TGF-ß) has been shown to inhibit myogenesis, yet the molecular mechanisms underlying such inhibition are not known. In the present study, TGF-ß was shown to inhibit myogenin and MEF2D expression and myotube formation in C2C12 myoblasts cultured in differentiation medium in a cell density–dependent manner. Transfection of C2C12 cells with Smad7, an antagonist for TGF-ß/Smad signaling, restored the capacity of these cells to differentiate in the presence of TGF-ß or when cultured in growth medium at low confluence, conditions that hinder muscle differentiation. Moreover, nocodazole, a microtubule-destabilizing agent, enhanced the inhibition of myogenesis exerted by TGF-ß, an effect that could be restored by tubulin-polymerizing agent taxol, both of which have been shown to affect Smad-microtubule interaction and regulate TGF-ß/Smad signaling. Our results indicate that TGF-ß inhibits myogenesis, at least in part, via Smad pathway, and provide evidence that low-dose pharmacological agents taxol and nocodazole can be used as a means to modulate myogenesis without affecting cell survival.
Key Words: myogenesis • transforming growth factor-ß • Smad • signal transduction • microtubules
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