Myogenin induces the myocyte-specific enhancer binding factor MEF-2 independently of other muscle-specific gene products.
The myocyte-specific enhancer-binding factor MEF-2 is a nuclear factor that interacts with a conserved element in the muscle creatine kinase and myosin light-chain 1/3 enhancers (L. A. Gossett, D. J. Kelvin, E. A. Sternberg, and E. N. Olson, Mol. Cell. Biol. 9:5022-5033, 1989). We show in this study that MEF-2 is regulated by the myogenic regulatory factor myogenin and that mitogenic signals block this regulatory interaction. Induction of MEF-2 by myogenin occurs in transfected 10T1/2 cells that have been converted to myoblasts by myogenin, as well as in CV-1 kidney cells that do not activate the myogenic program in response to myogenin. Through mutagenesis of the MEF-2 site, we further defined the binding site requirements for MEF-2 and identified potential MEF-2 sites within numerous muscle-specific regulatory regions. The MEF-2 site was also found to bind a ubiquitous nuclear factor whose binding specificity was similar to but distinct from that of MEF-2. Our results reveal that MEF-2 is controlled, either directly or indirectly, by a myogenin-dependent regulatory pathway and suggest that growth factor signals suppress MEF-2 expression through repression of myogenin expression or activity. The ability of myogenin to induce MEF-2 activity in CV-1 cells, which do not activate downstream genes associated with terminal differentiation, also demonstrates that myogenin retains limited function within cell types that are nonpermissive for myogenesis and suggests that MEF-2 is regulated independently of other muscle-specific genes.
Cserjesi
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Department of Biochemistry and Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Olson
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D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D003402:Creatine Kinase / Q000235:genetics; D004252:DNA Mutational Analysis; D003907:Dexamethasone / Q000494:pharmacology; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D000882:Haplorhini; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018008:Myogenin; D009218:Myosins / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D016415:Sequence Alignment; D014407:Tumor Cells, Cultured
C503799:MYOG protein, human; D009124:Muscle Proteins; C503801:Myog protein, mouse; D018008:Myogenin; D009687:Nuclear Proteins; D003907:Dexamethasone; D003402:Creatine Kinase; D009218:Myosins; D015689:Oncogene Protein p21(ras)