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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Animals
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Biological Transport
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COS Cells
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cell Differentiation
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Cell Line
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Cell Nucleus / metabolism
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Chlorocebus aethiops
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Cyclin D2
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Cyclin D3
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases / genetics
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Cyclin-Dependent Kinases / metabolism*
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Cyclins / genetics
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Cyclins / metabolism*
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Cytoplasm / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Helix-Loop-Helix Motifs*
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism
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MEF2 Transcription Factors
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Mice
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Muscle, Skeletal / cytology*
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Myogenic Regulatory Factors / genetics
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Myogenic Regulatory Factors / metabolism*
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Nuclear Receptor Coactivator 2
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Proto-Oncogene Proteins*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Transcriptional Activation
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Transfection
Substances
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Ccnd2 protein, mouse
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Ccnd3 protein, mouse
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Cyclin D2
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Cyclin D3
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Cyclins
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DNA-Binding Proteins
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MEF2 Transcription Factors
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Mef2c protein, mouse
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Myogenic Regulatory Factors
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Ncoa2 protein, mouse
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Nuclear Receptor Coactivator 2
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Transcription Factors
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Cyclin D1
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Calcium-Calmodulin-Dependent Protein Kinase Type 4
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Calcium-Calmodulin-Dependent Protein Kinases
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Camk4 protein, mouse
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Cdk4 protein, mouse
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases
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Hdac7 protein, mouse
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Histone Deacetylases