Reconstitution of cyclin D1-associated kinase activity drives terminally differentiated cells into the cell cycle
Reconstitution of cyclin D1-associated kinase activity drives terminally differentiated cells into the cell cycle
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DOI：
10.1128/mcb.21.16.5631-5643.2001
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发表时间：
2001-08-01
影响因子：
5.3
通讯作者：
Crescenzi, M
中科院分区：
文献类型：
--
作者：
Latella, L;Sacco, A;Crescenzi, M
终末细胞分化需要最终退出细胞周期。尽管成年哺乳动物的大多数细胞都是终末分化的，但保存有丝分裂后状态的分子机制尚不清楚。末梢分化骨骼肌细胞，或称肌管，是一个典型的末梢分化系统。我们之前发现了一个中期g(1)阻滞，阻止肌管在细胞周期中超过这一点。在这项工作中，我们开始定义这种块的分子基础。研究表明，肌管中高度活跃的细胞周期蛋白E和cdk2的过度表达诱导了pRb的磷酸化，但不能重新激活DNA合成，这强调了有丝分裂后细胞周期控制的严紧性。相反，在肌管中强制表达cyclin D1和野生型或显性阴性cdk4可以恢复cdk4激酶活性的生理水平，从而允许细胞周期的进展。这种再激活发生在原发肌管中。以及已建立的C2C12成肌细胞，并伴有肌肉特异性基因表达的损伤。其他终末分化系统如脂肪细胞和神经细胞也同样被重新激活。因此，目前的结果表明，抑制细胞周期蛋白dl相关激酶活性对于维持广泛分化的终分化细胞类型的有丝分裂后状态至关重要。
Terminal cell differentiation entails definitive withdrawal from the cell cycle. Although most of the cells of an adult mammal are terminally differentiated, the molecular mechanisms preserving the postmitotic state are insufficiently understood. Terminally differentiated skeletal muscle cells, or myotubes, are a prototypic terminally differentiated system. We previously identified a mid-G(1) block preventing myotubes from progressing beyond this point in the cell cycle. In this work, we set out to define the molecular basis of such a block. It is shown here that overexpression of highly active cyclin E and cdk2 in myotubes induces phosphorylation of pRb but cannot reactivate DNA synthesis, underscoring the tightness of cell cycle control in postmitotic cells. In contrast, forced expression of cyclin D1 and wild-type or dominant-negative cdk4 in myotubes restores physiological levels of cdk4 kinase activity, allowing progression through the cell cycle. Such reactivation occurs in myotubes derived from primary., as well as established, C2C12 myoblasts and is accompanied by impairment of muscle-specific gene expression. Other terminally differentiated systems as diverse as adipocytes and nerve cells are similarly reactivated. Thus, the present results indicate that the suppression of cyclin Dl-associated kinase activity is of crucial importance for the maintenance of the postmitotic state in widely divergent terminally differentiated cell types.