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首页> 外文学位 >Modulation of ErbB receptor signaling and cell cycle regulation by the deubiquitinating enzyme USP8.
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Modulation of ErbB receptor signaling and cell cycle regulation by the deubiquitinating enzyme USP8.

机译：去泛素化酶USP8对ErbB受体信号转导和细胞周期调控的调节。

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摘要

Ubiquitination is a dynamic and balanced process that is carried out by a series of ubiquitin-protein conjugating enzymes and deubiquitinating enzymes. Recently, deubiquitinating enzymes have been recognized to play an increasing number of novel roles in biological functions, including protein degradation, cell cycle control, endocytosis and DNA repair.;Our observations reveal the mechanism by which USP8 regulates ErbB receptor signaling and cell cycle progression, and contribute to the further understanding of the functions of substrate specific deubiquitinating enzymes.;USP8 is a novel deubiquitinating enzyme identified as a negative regulator of ErbB receptor signaling and cell growth. However, it remains unclear how USP8 performs the regulating functions. In my thesis, I demonstrate that a neuregulin (NRG) 1-induced protein stability cascade involving USP8 and Nrdp1 mediates the down-regulation of ErbB3 through PI3K pathway. NRG1 stimulation remarkably enhances Nrdp1 stabilization, which in turn leads to the degradation of ErbB3. Furthermore, I provide evidence that USP8 regulates cell cycle progression through the binding to 14-3-3 proteins. USP8 interacts weakly with 14-3-3 proteins during interphase. With the help of nuclear localization sequence (NLS), USP8 can be transported into the nucleus where it deubiquitinates specific substrates to prevent cells from proceeding into mitosis. In contrast, enhancement of 14-3-3 binding during mitosis sequesters USP8 in the cytosol, limits its access to nuclear substrates, and thereby allows the cell cycle to proceed.
机译：泛素化是由一系列泛素-蛋白质结合酶和去泛素化酶进行的动态且平衡的过程。近年来，已发现去泛素化酶在生物学功能中起着越来越多的新作用，包括蛋白质降解，细胞周期控制，内吞作用和DNA修复。我们的观察揭示了USP8调节ErbB受体信号传导和细胞周期进程的机制， ； USP8是一种新型的去泛素化酶，被鉴定为ErbB受体信号传导和细胞生长的负调节剂。但是，尚不清楚USP8如何执行调节功能。在我的论文中，我证明了神经调节蛋白（NRG）1诱导的涉及USP8和Nrdp1的蛋白稳定性级联通过PI3K途径介导了ErbB3的下调。 NRG1刺激显着增强了Nrdp1的稳定性，进而导致ErbB3的降解。此外，我提供的证据表明USP8通过与14-3-3蛋白结合来调节细胞周期进程。在相间期，USP8与14-3-3蛋白的相互作用较弱。借助核定位序列（NLS），USP8可以转运到细胞核中，在该处去泛素化特定的底物，以防止细胞进入有丝分裂状态。相反，在有丝分裂期间14-3-3结合的增强将USP8隔离在胞质溶胶中，限制了其进入核底物的通道，从而使细胞周期得以进行。

著录项

  • 作者

    Cao, Zhongwei.;

  • 作者单位

    University of California, Davis.;

  • 授予单位 University of California, Davis.;
  • 学科 Biology Cell.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 160 p.
  • 总页数 160
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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