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首页> 外文学位 >Chromosome Instability Underlies Hematopoietic Stem Cell Dysfunction and Lymphoid Neoplasia Associated with Impaired Fbw7-mediated Cyclin E Regulation.
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Chromosome Instability Underlies Hematopoietic Stem Cell Dysfunction and Lymphoid Neoplasia Associated with Impaired Fbw7-mediated Cyclin E Regulation.

机译：染色体不稳定是造血干细胞功能障碍和淋巴瘤形成与Fbw7介导的细胞周期蛋白E调节受损相关的基础。

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摘要

The Fbw7 ubiquitin ligase critically regulates hematopoietic stem cell (HSC) function, though the precise contribution of individual substrate ubiquitination pathways to HSC homeostasis is unknown. In the work reported here, we used a mouse model in which we introduced two knock-in mutations (T74A and T393A [changes of threonine to alanine at positions 74 and 393]) to disrupt Fbw7-dependent regulation of cyclin E, its prototypic substrate, and to examine the consequences of cyclin E dysregulation for HSC function. Serial transplantation revealed that cyclin ET74A T393A HSCs self-renewed normally; however, we identified defects in their multi-lineage reconstituting capacity. By inducing hematologic stress, we exposed an impaired self-renewal phenotype in cyclin E knock-in HSCs that was associated with defective cell cycle exit and the emergence of chromosome instability (CIN). Importantly, deregulated cyclin E in hematopoietic cells induced p53. Thus, we studied the effect of p53-loss on cyclin ET74A T393A HSCs. Cyclin ET74A T393A; p53-null HSCs exhibited defects in both self-renewal and multi-lineage reconstitution. By enumerating chromosomes in metaphase spreads, we found cyclin ET74A T393A; p53-null hematopoietic stem and progenitor cells (HSPCs) demonstrated significant CIN. Moreover, CIN was a characteristic feature of fatal T-cell malignancies that ultimately developed in recipients of cyclin ET74A T393A; p53-null HSCs. In thymocytes isolated from recipients of cyclin ET74A T393A ; p53-null HSCs, CIN was associated with the marked potentiation of cyclin E kinase activity by p53- or p21-loss. Together, our findings demonstrate the importance of Fbw7-dependent cyclin E control to the hematopoietic system and highlight CIN as a characteristic feature of HSC dysfunction and malignancy induced by deregulated cyclin E in vivo.
机译：Fbw7泛素连接酶可严格调节造血干细胞（HSC）功能，尽管单个底物泛素化途径对HSC稳态的精确贡献尚不清楚。在这里报道的工作中，我们使用了一个小鼠模型，在该模型中我们引入了两个敲入突变（T74A和T393A [在74和393位的苏氨酸向丙氨酸的变化]）来破坏Fbw7依赖性的细胞周期蛋白E（其原型底物）的调控，并研究细胞周期蛋白E失调对HSC功能的影响。连续移植表明，细胞周期蛋白ET74A T393A HSC正常自我更新。但是，我们发现了其多谱系重构能力方面的缺陷。通过诱导血液学应激，我们暴露了细胞周期蛋白E敲入HSC中受损的自我更新表型，这与细胞周期缺陷退出和染色体不稳定性（CIN）的出现有关。重要的是，造血细胞中细胞周期蛋白E的失调诱导了p53。因此，我们研究了p53丢失对细胞周期蛋白ET74A T393A HSC的影响。细胞周期蛋白ET74A T393A; p53-null HSCs在自我更新和多谱系重构中均表现出缺陷。通过计数中期扩散中的染色体，我们发现了细胞周期蛋白ET74A T393A。 p53无效的造血干细胞和祖细胞（HSPC）显示出显着的CIN。此外，CIN是致命的T细胞恶性肿瘤的特征性特征，该恶性肿瘤最终在细胞周期蛋白ET74A T393A的受体中发展； p53无效的HSC。在分离自cyclin ET74A T393A受体的胸腺细胞中; p53缺失的HSC，CIN与p53或p21缺失引起的细胞周期蛋白E激酶活性显着增强有关。在一起，我们的研究结果表明依赖Fbw7的细胞周期蛋白E控制对造血系统的重要性，并强调CIN是体内细胞周期蛋白E失控诱导的HSC功能障碍和恶性肿瘤的特征。

著录项

  • 作者

    Siu, Ka Tat.;

  • 作者单位

    Northwestern University.;

  • 授予单位 Northwestern University.;
  • 学科 Biology Genetics.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2014
  • 页码 103 p.
  • 总页数 103
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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