title: The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis.
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.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9148, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Zhang
authors.forename: T A
authors.initials: TA
authors.lastname: McKinsey
authors.forename: E N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D048948:14-3-3 Proteins; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000378:metabolism; D005314:Embryonic and Fetal Development; D018507:Gene Expression Regulation, Developmental; D006655:Histone Deacetylases / Q000378:metabolism; D064326:MEF2 Transcription Factors; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000196:embryology / Q000502:physiology*; D017570:MyoD Protein / Q000378:metabolism; D018006:Myogenic Regulatory Factors; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D017570:MyoD Protein; D018006:Myogenic Regulatory Factors; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; C400300:HDAC4 protein, human; C486544:HDAC9 protein, human; C498618:Hdac5 protein, mouse; C486545:Hdac9 protein, mouse; D006655:Histone Deacetylases