The Rb-CDK4/6 signaling pathway is critical in neural precursor cell cycle regulation
The Rb-CDK4/6 signaling pathway is critical in neural precursor cell cycle regulation
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DOI：
10.1074/jbc.m004879200
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发表时间：
2000-10-27
影响因子：
4.8
通讯作者：
Slack, RS
中科院分区：
文献类型：
--
作者：
Ferguson, KL;Callaghan, SM;Slack, RS
肿瘤抑制因子视网膜母细胞瘤（Rb）参与终末有丝分裂和神经元分化。我们假设Rb通路的激活将诱导原代神经前体细胞的细胞周期停滞，而不依赖于细胞周期蛋白依赖性激酶4/6（CDK 4/6）的功能，即从CDK 2中分离CIP/KIP CDK抑制剂（CKIs）p21和p27。在来源于E12.5野生型和Rb缺陷型小鼠胚胎的神经祖细胞中的dnCDK 2、dnCDK 4和dnCDK 6。与以前的研究相比，我们的结果表明，除了dnCDK 2，dnCDK 4/6突变体可以诱导生长停滞。此外，dnCDK 4/6介导的抑制是Rb依赖性的。dnCDK 2部分抑制Rb缺陷细胞中的细胞生长，表明CDK 2可能具有额外的靶点。先前提出的CDK 4/6的功能是CKI螯合，从而防止产生的对CDK 2的抑制，CDK 2被认为是细胞周期的关键调节因子。然而，我们的免疫沉淀显示，显性负性CDK突变体可以阻止细胞生长，尽管它们与p21和p27的相互作用，总之，我们的结果表明，CDK 2和CDK 4/6是至关重要的细胞周期调控。此外，我们的数据强调了Rb调控途径在神经元发育和细胞周期调控中的重要性，独立于CRI隔离。
The tumor suppressor, retinoblastoma (Rb), is involved in both terminal mitosis and neuronal differentiation. We hypothesized that activation of the Rb pathway would induce cell cycle arrest in primary neural precursor cells, independent of the proposed function of cyclin-dependent kinases 4/6 (CDK4/6) to sequester the CIP/KIP CDK inhibitors (CKIs) p21 and p27 from CDK2, We expressed dominant negative adenovirus mutants of CDKs 2, 4, and 6 (dnCDK2, dnCDK4, and dnCDK6) in neural progenitor cells derived from E12.5 wild type and Rb-deficient mouse embryos. In contrast to previous studies, our results demonstrate that in addition to dnCDK2, the dnCDK4/6 mutants can induce growth arrest. Moreover, the dnCDK4/6-mediated inhibition is Rb-dependent. The dnCDK2 partially inhibited cell growth in Rb-deficient cells, suggesting that CDK2 may have additional targets, A previously proposed function of CDK4/6 is CKI sequestration, thereby preventing the resulting inhibition of CDK2, believed to be the key regulator of cell cycle. However, our immunoprecipitations revealed that the dominant negative CDK mutants could arrest cell growth despite their interaction with p21 and p27, Taken together, our results demonstrate that both CDK2 and CDK4/6 are crucial for cell cycle regulation. Furthermore, our data underscore the importance of the Rb regulatory pathway in neuronal development and cell cycle regulation, independent of CRI sequestration.