1. The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis.
- Author
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Zhang CL, McKinsey TA, and Olson EN
- Subjects
- 14-3-3 Proteins, Animals, COS Cells, Cell Differentiation, Cell Line, Chlorocebus aethiops, DNA-Binding Proteins metabolism, Histone Deacetylases metabolism, MEF2 Transcription Factors, Mice, Muscle, Skeletal cytology, Muscle, Skeletal embryology, MyoD Protein metabolism, Myogenic Regulatory Factors, Recombinant Proteins metabolism, Repressor Proteins genetics, Repressor Proteins metabolism, Signal Transduction, Transcription Factors metabolism, Transcription, Genetic, Transfection, Tyrosine 3-Monooxygenase metabolism, Carrier Proteins genetics, Carrier Proteins metabolism, Embryonic and Fetal Development, Gene Expression Regulation, Developmental, Muscle, Skeletal physiology
- Abstract
Activation of muscle-specific genes by members of the myocyte enhancer factor 2 (MEF2) and MyoD families of transcription factors is coupled to histone acetylation and is inhibited by class II histone deacetylases (HDACs) 4 and 5, which interact with MEF2. The ability of HDAC4 and -5 to inhibit MEF2 is blocked by phosphorylation of these HDACs at two conserved serine residues, which creates docking sites for the intracellular chaperone protein 14-3-3. When bound to 14-3-3, HDACs are released from MEF2 and transported to the cytoplasm, thereby allowing MEF2 to stimulate muscle-specific gene expression. MEF2-interacting transcription repressor (MITR) shares homology with the amino-terminal regions of HDAC4 and -5, but lacks an HDAC catalytic domain. Despite the absence of intrinsic HDAC activity, MITR acts as a potent inhibitor of MEF2-dependent transcription. Paradoxically, however, MITR has minimal inhibitory effects on the skeletal muscle differentiation program. We show that a substitution mutant of MITR containing alanine in place of two serine residues, Ser-218 and Ser-448, acts as a potent repressor of myogenesis. Our findings indicate that promyogenic signals antagonize the inhibitory action of MITR by targeting these serines for phosphorylation. Phosphorylation of Ser-218 and Ser-448 stimulates binding of 14-3-3 to MITR, disrupts MEF2:MITR interactions, and alters the nuclear distribution of MITR. These results reveal a role for MITR as a signal-dependent regulator of muscle differentiation.
- Published
- 2001
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