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Molecular and Cellular Biology, April 1999, p. 2853-2862, Vol. 19, No. 4
Department of Molecular Biology and Oncology,
The University of Texas Southwestern Medical Center at Dallas,
Dallas, Texas 75235-9148
Received 17 June 1998/Returned for modification 5 August
1998/Accepted 15 December 1998
Skeletal muscle gene expression is dependent on combinatorial
associations between members of the MyoD family of basic
helix-loop-helix (bHLH) transcription factors and the myocyte enhancer
factor 2 (MEF2) family of MADS-box transcription factors. The
transmembrane receptor Notch interferes with the muscle-inducing
activity of myogenic bHLH proteins, and it has been suggested that this
inhibitory activity of Notch is directed at an essential cofactor that
recognizes the DNA binding domains of the myogenic bHLH proteins. Given
that MEF2 proteins interact with the DNA binding domains of myogenic bHLH factors to cooperatively regulate myogenesis, we
investigated whether members of the MEF2 family might serve as targets
for the inhibitory effects of Notch on myogenesis. We show that a constitutively activated form of Notch specifically blocks DNA binding
by MEF2C, as well as its ability to cooperate with MyoD and myogenin to
activate myogenesis. Responsiveness to Notch requires a 12-amino-acid
region of MEF2C immediately adjacent to the DNA binding domain that is
unique to this MEF2 isoform. Two-hybrid assays and
coimmunoprecipitations show that this region of MEF2C interacts
directly with the ankyrin repeat region of Notch. These findings reveal
a novel mechanism for Notch-mediated inhibition of myogenesis
and demonstrate that the Notch signaling pathway can discriminate
between different members of the MEF2 family.
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Activated Notch Inhibits Myogenic Activity of the
MADS-Box Transcription Factor Myocyte Enhancer Factor 2C


*
Corresponding author. Mailing address: Department of
Molecular Biology and Oncology, The University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Blvd., Dallas, TX
75235-9148. Phone: (214) 648-1187. Fax: (214) 648-1196. E-mail:
eolson{at}hamon.swmed.edu.
Present address: Department of Biology, Arizona State University,
Tempe, AZ 85287-1501.
Present address: Children's Hospital Medical Center, Division of
Molecular Cardiovascular Biology, Cincinnati, OH 45229-3039.
§
Present address: Cardiovascular Research Institute, University of
California San Francisco, San Francisco, CA 94143.
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