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Mirk/dyrk1B decreases the nuclear accumulation of class II histone deacetylases during skeletal muscle differentiation.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2005 Feb 11; Vol. 280 (6), pp. 4894-905. Date of Electronic Publication: 2004 Nov 16. - Publication Year :
- 2005
-
Abstract
- Mirk/dyrk1B is a member of the dyrk/minibrain family of serine/threonine kinases that mediate the transition from growth to differentiation in lower eukaryotes and mammals. Depletion of endogenous Mirk from C2C12 myoblasts by RNA interference blocks skeletal muscle differentiation (Deng, X., Ewton, D., Pawlikowski, B., Maimone, M., and Friedman, E. (2003) J. Biol. Chem. 278, 41347-41354). We now demonstrate that knockdown of Mirk blocks transcription of the muscle regulatory factor myogenin. Co-expression of Mirk with MEF2C, but not MyoD or Myf5, enhanced activation of the myogenin promoter in a Mirk kinase-dependent manner. Mirk activated MEF2 not through direct phosphorylation of MEF2 but by phosphorylation of its inhibitors, the class II histone deacetylases (HDACs). MEF2 is sequestered by class II HDACs such as HDAC5 and MEF2-interacting transcriptional repressor (MITR). Mirk antagonized the inhibition of MEF2C by MITR, whereas kinase-inactive Mirk was ineffective. Mirk phosphorylates class II HDACs at a conserved site within the nuclear localization region, reducing their nuclear accumulation in a dose-dependent and kinase-dependent manner. Moreover, less mutant MITR phosphomimetic at the Mirk phosphorylation site localized in the nucleus than wild-type MITR. Regulation of class II HDACs occurs by multiple mechanisms. Others have shown that calcium signaling leads to phosphorylation of HDACs at 14-3-3-binding sites, blocking their association with MEF2 within the nucleus. Mirk provides another level of regulation. Mirk is induced within the initial 24 h of myogenic differentiation and enables MEF2 to transcribe the myogenin gene by decreasing the nuclear accumulation of class II HDACs.
- Subjects :
- Amino Acid Sequence
Animals
Binding Sites
Blotting, Northern
Butyrates pharmacology
Cell Differentiation
Cell Line
DNA chemistry
DNA-Binding Proteins metabolism
Dose-Response Relationship, Drug
Down-Regulation
Electrophoresis, Polyacrylamide Gel
Glutathione Transferase metabolism
Luciferases metabolism
MEF2 Transcription Factors
Mice
Molecular Sequence Data
Muscle Proteins metabolism
Muscle, Skeletal metabolism
MyoD Protein metabolism
Myogenic Regulatory Factor 5
Myogenic Regulatory Factors metabolism
Myogenin genetics
NIH 3T3 Cells
Oligonucleotide Array Sequence Analysis
Phosphorylation
Plasmids metabolism
Promoter Regions, Genetic
RNA Interference
RNA, Messenger metabolism
RNA, Small Interfering metabolism
Recombinant Fusion Proteins metabolism
Sequence Homology, Amino Acid
Subcellular Fractions
Trans-Activators metabolism
Transcription Factors
Transcription, Genetic
Transfection
Up-Regulation
Dyrk Kinases
Cell Nucleus metabolism
Gene Expression Regulation, Enzymologic
Histone Deacetylases metabolism
Mitogen-Activated Protein Kinases biosynthesis
Muscle, Skeletal cytology
Myogenin metabolism
Protein Serine-Threonine Kinases biosynthesis
Protein-Tyrosine Kinases biosynthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 280
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15546868
- Full Text :
- https://doi.org/10.1074/jbc.M411894200