Cyclin D-cdk4 activity modulates the subnuclear localization and interaction of MEF2 with SRC-family coactivators during skeletal muscle differentiation
Cyclin D-cdk4 activity modulates the subnuclear localization and interaction of MEF2 with SRC-family coactivators during skeletal muscle differentiation
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DOI：
10.1101/gad.u-9988r
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发表时间：
2002-07-15
影响因子：
10.5
通讯作者：
Lassar, AB
中科院分区：
文献类型：
--
作者：
Lazaro, JB;Bailey, PJ;Lassar, AB
以前的工作表明，D型细胞周期蛋白-CDK4复合体只在增殖细胞中活跃，可以抑制增殖的成肌细胞中的骨骼肌分化计划。在本研究中，我们发现细胞周期蛋白D-cdk的活性可以阻断转录调控因子MEF2家族的活性，而MEF2家族是骨骼肌基因表达的关键调控因子。我们发现，周期蛋白D-cdk的活性阻断了MEF2C与共激活蛋白GRIP-1的联系，从而抑制了MEF2的活性。在骨骼肌分化过程中，GRIP-1定位于定位于核结构，并能明显地将MEF2拴在这些结构上。共转染GRIP-1既能增强Gal4-MEF2C结构的转录活性，又能诱导MEF2C定位于核结构。与在增殖的成肌细胞中缺乏点状核GRIP-1一致，我们发现异位周期蛋白D-CDK4的表达破坏了GRIP-1和MEF2C在这些点状亚核结构上的定位。我们的发现表明，细胞周期蛋白D-CDK4的活性通过阻断MEF2与辅活化子GRIP-1的联系来抑制增殖细胞中骨骼肌的分化，并伴随着破坏这些因子与细胞内点状核亚域的联系。
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.