Inhibition of myogenesis by multiple cyclin-Cdk complexes - Coordinate regulation of myogenesis and cell cycle activity at the level of E2F
Inhibition of myogenesis by multiple cyclin-Cdk complexes - Coordinate regulation of myogenesis and cell cycle activity at the level of E2F
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DOI：
10.1074/jbc.272.2.791
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发表时间：
1997-01-10
影响因子：
4.8
通讯作者：
Walsh, K
中科院分区：
文献类型：
--
作者：
Guo, K;Walsh, K
在骨骼肌发生过程中，细胞周期的退出伴随着收缩表型的表达。在这里，我们表明，异位表达的每个D型细胞周期蛋白是足以抑制肌肉特异性肌酸激酶（MCK）基因的转录激活。相反，细胞周期蛋白A或细胞周期蛋白E的异位表达抑制MCK的表达，只有当它们与它们的催化伙伴细胞周期蛋白依赖性激酶2（Cdk 2）共表达。对于这些条件中的每一个，肌原性转录抑制通过一般Cdk抑制剂p21的异位共表达来逆转。细胞周期蛋白或细胞周期蛋白-Cdk组合对MCK表达的抑制与E2 F激活相关，表明这种抑制是由Cdk复合物的总体Rb-激酶活性介导的。在支持这一假设，一个过度活跃的突变体Rb被发现部分逆转MCK表达的抑制细胞周期蛋白D1和细胞周期蛋白A和Cdk 2的组合。这些数据表明，肌原性转录活性的抑制是整体Cdk活性的一般特征，其至少部分由口袋蛋白/E2 F依赖性途径介导，MCK启动子活性也被异位E2 F1表达抑制，但这种抑制不被p21的共表达逆转。对一系列E2 F1突变体的分析表明，转录激活、亮氨酸拉链、碱性和细胞周期蛋白A/Cdk 2结合结构域是不稳定的，但螺旋-环-螺旋区域是生肌抑制所必需的。这些数据表明，肌细胞的增殖和分化是协调在E2 F的水平，这些相反的活动是由不同的E2 F域调节。
During skeletal myogenesis, cell cycle withdrawal accompanies the expression of the contractile phenotype. Here we show that ectopic expression of each D-type cyclin is sufficient to inhibit the transcriptional activation of the muscle-specific creatine kinase (MCK) gene. In contrast, ectopic expression of cyclin A or cyclin E inhibits MCK expression only when they are co-expressed with their catalytic partner cyclin-dependent kinase 2 (Cdk2). For each of these conditions, myogenic transcriptional inhibition is reversed by the ectopic co-expression of the general Cdk inhibitor p21. Inhibition of MCK expression by cyclins or cyclin-Cdk combinations correlates with E2F activation, suggesting that the inhibition is mediated by the overall Rb-kinase activities of the Cdk complexes. In support of this hypothesis, a hyperactive mutant of Rb was found to partially re verse the inhibition of MCK expression by cyclin D1 and by the combination of cyclin A and Cdk2. These data demonstrate that the inhibition of myogenic transcriptional activity is a general feature of overall Cdk activity which is mediated, at least in part, by an pocket protein/E2F-dependent pathway, MCK promoter activity is also inhibited by ectopic E2F1 expression, but this inhibition is not reversed by the co-expression of p21. Analyses of a series of E2F1 mutants revealed that the transcriptional activation, leucine zipper, basic, and cyclin A/Cdk2-binding domains are dispensable, but the helix-loop-helix region is essential for myogenic inhibition. These data demonstrate that myocyte proliferation and differentiation are coordinated at the level of E2F and that these opposing activities are regulated by different E2F domains.