INHIBITION OF MYOGENESIS BY TRANSFORMING-GROWTH-FACTOR-BETA IS DENSITY-DEPENDENT AND RELATED TO THE TRANSLOCATION OF TRANSCRIPTION FACTOR MEF2 TO THE CYTOPLASM
L. Deangelis et al., INHIBITION OF MYOGENESIS BY TRANSFORMING-GROWTH-FACTOR-BETA IS DENSITY-DEPENDENT AND RELATED TO THE TRANSLOCATION OF TRANSCRIPTION FACTOR MEF2 TO THE CYTOPLASM, Proceedings of the National Academy of Sciences of the United Statesof America, 95(21), 1998, pp. 12358-12363
Transforming growth factor beta (TGF-beta) was found to inhibit differ
entiation of myogenic cells only when they were grown to high density.
Inhibition also occurred when myogenic cells were cocultured with oth
er types of mesenchymal cells but not when they were cocultured with e
pithelial cells. It is therefore possible that some density-dependent
signaling mediates the intracellular response to TGF-beta. Within 30 m
in of treatment, TGF-beta induced translocation of MEF2, but not MyoD,
myogenin, or p21, to the cytoplasm of myogenic cells grown to high de
nsity. Translocation was reversible on withdrawal of TGF-beta. By usin
g immune electron microscopy and Western blot analysis on subcellular
fractions, MEF2 was shown to be tightly associated with cytoskeleton m
embrane components. To test whether MEF2 export from the nucleus was c
ausally related to the inhibitory action of TGF-beta, we transfected C
2C12 myoblasts with MEF2C containing the nuclear localization signal o
f simian virus 40 large T antigen (nlsSV40). Myogenic cells expressing
the chimerical MEF2C/nlsSV40, but not wild-type MEF2C, retained this
transcription factor in the nucleus and were resistant to the inhibito
ry action of TGF-beta. We propose a mechanism in which the inhibition
of myogenesis by TGF-beta is mediated through MEF2 localization to the
cytoplasm, thus preventing it from participating in an active transcr
iptional complex.