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Nuclear function of Smad7 promotes myogenesis

Tetsuaki Miyake1, Nezeka S Alli, John C McDermott

  • 1Department of Biology, York University, St., Toronto, Ontario M3J 1P3, Canada.

Molecular and Cellular Biology
|December 10, 2009
PubMed

Insights

Smad7 promotes muscle cell differentiation independently of TGF-beta signaling. This nuclear Smad7 function interacts with MyoD, enhancing muscle gene activation and overcoming inhibitory signals.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Muscle Development

Background:

  • The canonical role of Smad7 in transforming growth factor beta (TGF-beta) signaling is inhibitory.
  • Smad7's previously reported promyogenic role in myogenic cells suggested functions beyond TGF-beta receptor inhibition.

Purpose of the Study:

  • To investigate the nuclear function of Smad7 in myogenesis, independent of its interaction with the TGF-beta receptor.
  • To elucidate the mechanism by which Smad7 promotes myogenic differentiation.

Main Methods:

  • Engineering of a Smad7-nuclear localization signal (NLS) chimera to ensure nuclear localization and bypass receptor binding.
  • Assays to assess Smad3 activation, myogenic gene activation, and phenotypic myogenesis.
  • Reporter and myogenic conversion assays to study Smad7's interaction with MyoD and MEK.

Main Results:

  • Smad7-NLS enhanced myogenic gene activation and phenotypic myogenesis without repressing Smad3 activation.
  • Smad7 physically interacts with MyoD and counteracts the inhibitory effects of active MEK on MyoD.
  • The balance between Smad7 and active MEK critically regulates MyoD transcriptional activity.

Conclusions:

  • Smad7 possesses a nuclear, TGF-beta-independent coactivator function essential for promoting myogenesis.
  • Smad7's interaction with MyoD and modulation of MEK signaling are key mechanisms underlying its promyogenic activity.

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