| First Author | Zhang CL | Year | 2001 |
| Journal | Proc Natl Acad Sci U S A | Volume | 98 |
| Issue | 13 | Pages | 7354-9 |
| PubMed ID | 11390982 | Mgi Jnum | J:70040 |
| Mgi Id | MGI:2136109 | Doi | 10.1073/pnas.131198498 |
| Citation | Zhang CL, et al. (2001) The transcriptional corepressor MITR is a signal-responsive inhibitor of myogenesis. Proc Natl Acad Sci U S A 98(13):7354-9 |
| abstractText | 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. |
