...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Cell cycle >GSK3 inhibitors stabilize Wee1 and reduce cerebellar granule cell progenitor proliferation
【24h】

GSK3 inhibitors stabilize Wee1 and reduce cerebellar granule cell progenitor proliferation

机译：GSK3抑制剂稳定Wee1并减少小脑颗粒细胞祖细胞增殖

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Ubiquitin mediated proteolysis is required for transition from one cell cycle phase to another. For instance, the mitosis inhibitor Wee1 is targeted for degradation during S phase and G2 to allow mitotic entry. Wee1 is an essential tyrosine kinase required for the G2/M transition and S-phase progression. Although several studies have concentrated on Wee1 regulation during mitosis, few have elucidated its degradation during interphase. Our prior studies have demonstrated that Wee1 is degraded via CK1 delta dependent phosphorylation during the S and G2/M phases of the cell cycle. Here we demonstrate that GSK3 beta may work in concert with CK1d to induce Wee1 destruction during interphase. We generated small molecules that specifically stabilized Wee1. We profiled these compounds against 296 kinases and found that they inhibit GSK3 alpha and GSK3 beta, suggesting that Wee1 may be targeted for proteolysis by GSK3. Consistent with this notion, known GSK3 inhibitors stabilized Wee1 and GSK3 beta depletion reduced Wee1 turnover. Given Wee1's central role in cell cycle progression, we predicted that GSK3 inhibitors should limit cell proliferation. Indeed, we demonstrate that GSK3 inhibitors potently inhibited proliferation of the most abundant cell in the mammalian brain, the cerebellar granule cell progenitor (GCP). These studies identify a previously unappreciated role for GSK3 beta-mediated regulation of Wee1 during the cell cycle and in neurogenesis. Furthermore, they suggest that pharmacological inhibition of Wee1 may be therapeutically attractive in some cancers where GSK-3 beta or Wee1 are dysregulated.
机译：从一个细胞周期阶段过渡到另一个阶段需要泛素介导的蛋白水解作用。例如，有丝分裂抑制剂Wee1的目标是在S期和G2期间降解，以允许有丝分裂进入。 Wee1是G2 / M过渡和S期进程所需的必需酪氨酸激酶。尽管有几项研究集中在有丝分裂期间的Wee1调控上，但很少有人阐明其在相间期的降解。我们的先前研究表明，在细胞周期的S和G2 / M阶段，Wee1通过CK1δ依赖性磷酸化而降解。在这里，我们证明GSK3 beta可能与CK1d协同作用，在相间诱导Wee1破坏。我们产生了能稳定Wee1的小分子。我们针对296种激酶对这些化合物进行了分析，发现它们抑制GSK3 alpha和GSK3 beta，表明Wee1可能是GSK3进行蛋白水解的目标。与该概念一致，已知的GSK3抑制剂可稳定Wee1和GSK3β的消耗，从而减少Wee1的周转率。鉴于Wee1在细胞周期进程中的核心作用，我们预测GSK3抑制剂应限制细胞增殖。实际上，我们证明了GSK3抑制剂有效抑制了哺乳动物脑中小脑颗粒细胞祖细胞（GCP）中最丰富的细胞的增殖。这些研究确定了在细胞周期和神经发生过程中，GSK3β介导的Wee1调控的作用，这一作用以前未被认识。此外，他们认为Wee1的药理抑制作用在某些GSK-3 beta或Wee1失调的癌症中可能具有治疗吸引力。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号