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PMID: 9770491 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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 States of America ·Vol. 95 ·No. 21 ·1998-10-13 ·Pages 12358-63

De Angelis L, Borghi S, Melchionna R, Berghella L, Baccarani-Contri M, Parise F, Ferrari S, Cossu G

Abstract

Transforming growth factor beta (TGF-beta) was found to inhibit differentiation of myogenic cells only when they were grown to high density. Inhibition also occurred when myogenic cells were cocultured with other types of mesenchymal cells but not when they were cocultured with epithelial cells. It is therefore possible that some density-dependent signaling mediates the intracellular response to TGF-beta. Within 30 min of treatment, TGF-beta induced translocation of MEF2, but not MyoD, myogenin, or p21, to the cytoplasm of myogenic cells grown to high density. Translocation was reversible on withdrawal of TGF-beta. By using immune electron microscopy and Western blot analysis on subcellular fractions, MEF2 was shown to be tightly associated with cytoskeleton membrane components. To test whether MEF2 export from the nucleus was causally related to the inhibitory action of TGF-beta, we transfected C2C12 myoblasts with MEF2C containing the nuclear localization signal of 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 inhibitory 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 transcriptional complex.

MeSH Terms
Animals Biological Transport Blotting, Western Cell Differentiation/physiology Cell Nucleus/metabolism Coculture Techniques Cytoplasm/metabolism DNA-Binding Proteins/metabolism MEF2 Transcription Factors Mice Mice, Transgenic Microscopy, Immunoelectron Muscle Development Muscles/cytology,metabolism Myogenic Regulatory Factors Transcription Factors/metabolism Transforming Growth Factor beta/physiology
Chemicals
DNA-Binding Proteins MEF2 Transcription Factors Mef2c protein, mouse Myogenic Regulatory Factors Transcription Factors Transforming Growth Factor beta
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
De Angelis L
Istituto Pasteur Fondazione Cenci-Bolognetti, Dipartimento di Istologia ed Embriologia Medica, Università di Roma La Sapienza, Via A, Scarpa 14, 00161 Rome, Italy.
Borghi S
Melchionna R
Berghella L
Baccarani-Contri M
Parise F
Ferrari S
Cossu G
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.21.12358
Published
1998-10-13
Pages
12358-63
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC22836
Subset
IM
Grants
Telethon · 948 · Italy
Telethon · A.067 · Italy
External Links
PubMed source DOI: 10.1073/pnas.95.21.12358 PMC Full Text View journal details
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