PMID:12130539

Citation	Lazaro, JB, Bailey, PJ and Lassar, AB (2002) Cyclin D-cdk4 activity modulates the subnuclear localization and interaction of MEF2 with SRC-family coactivators during skeletal muscle differentiation. Genes Dev. 16:1792-805
Abstract	Prior work has indicated that D-type cyclin-cdk4 complexes, which are only active in proliferating cells, can suppress the skeletal muscle differentiation program in proliferating myoblasts. In this study, we show that cyclin D-cdk activity can block the activity of the MEF2 family of transcriptional regulators, which are crucial regulators of skeletal muscle gene expression. We have found that cyclin D-cdk activity blocks the association of MEF2C with the coactivator protein GRIP-1 and thereby inhibits the activity of MEF2. During skeletal muscle differentiation, GRIP-1 is localized to punctate nuclear structures and can apparently tether MEF2 to such structures. Cotransfection of GRIP-1 can both potentiate the transcriptional activity of a Gal4-MEF2C construct and induce MEF2C localization to punctate nuclear structures. Consistent with the absence of punctate nuclear GRIP-1 in proliferating myoblasts, we have found that ectopic cyclin D-cdk4 expression disrupts the localization of both GRIP-1 and MEF2C to these punctate subnuclear structures. Our findings indicate that cyclin D-cdk4 activity represses skeletal muscle differentiation in proliferating cells by blocking the association of MEF2 with the coactivator GRIP-1 and concomitantly disrupts the association of these factors with punctate nuclear subdomains within the cell.
Links	PubMed PMC186397 Online version:10.1101/gad.U-9988R
Keywords	3T3 Cells; Animals; Biological Transport; COS Cells; Calcium-Calmodulin-Dependent Protein Kinase Type 4; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Cell Differentiation; Cell Line; Cell Nucleus/metabolism; Cercopithecus aethiops; Cyclin D1/genetics; Cyclin D1/metabolism; Cyclin D2; Cyclin D3; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinases/genetics; Cyclin-Dependent Kinases/metabolism; Cyclins/genetics; Cyclins/metabolism; Cytoplasm/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Helix-Loop-Helix Motifs; Histone Deacetylases/genetics; Histone Deacetylases/metabolism; Mice; Muscle, Skeletal/cytology; Myogenic Regulatory Factors/genetics; Myogenic Regulatory Factors/metabolism; Nuclear Receptor Coactivator 2; Proto-Oncogene Proteins; Recombinant Fusion Proteins/genetics; Recombinant Fusion Proteins/metabolism; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic; Transcriptional Activation; Transfection
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