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E2F couples proliferation to anti-proliferation.

机译：E2F将增殖与抗扩散结合在一起。

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摘要

The E2F transcription factor family determines cellular fate and physiology by controlling gene expression of key cell-cycle regulators. In this dissertation, we show mechanistically how multiple biological processes are interconnected to provide a coordinated response when needed. Specifically, that anti-proliferation is ‘hardwired’ to proliferation by virtue of E2F-1.; It is documented that unrestrained E2F activity forces S phase entry and promotes apoptosis through p53-dependent and -independent mechanisms. Here, we demonstrate that deregulation of E2F by adenovirus E1A, Rb loss or enforced E2F-1 expression results in the accumulation of caspase pro-enzymes through a direct transcriptional mechanism. In addition, increased caspase levels potentiate cell death in the presence of p53-generated signals that trigger caspase activation. Our results reveal that mitogenic oncogenes engage a tumor suppressor network that acts at multiple levels to efficiently induce cell death. Importantly, this work provides an explanation of how cell cycle progression can be coupled to the apoptotic machinery.; Genomic instability and aneuploidy are common features of human tumors. Although aneuploidy is believed to arise in most cases from defects in mitotic checkpoints, loss of function mutations in checkpoint components are very rare. In this study, we also show that the mitotic checkpoint protein Mad2 is regulated by E2F transcription factors and, as a consequence, is inappropriately expressed throughout the cell cycle in cells with defects in the Rb pathway. Generation of Rb pathway lesions in normal cells produces aberrant Mad2 expression, and correlates with checkpoint defects leading to polyploidy. These same defects can be recapitulated by merely enforcing expression of Mad2. Consistently, Mad2 induced expression accelerates tumorigenesis in the Eμ-myc lymphoma mouse model. Taken together, these results suggest that aneuploidy arise as a byproduct of defects in cell cycle control that simultaneously compromise the spindle checkpoint. This study provides a new model to explain the appearance of aneuploidy in human cancer.
机译：E2F转录因子家族通过控制关键细胞周期调节因子的基因表达来决定细胞命运和生理。在本文中，我们机械地显示了多个生物过程如何相互联系，以在需要时提供协调的响应。具体而言，由于E2F-1，这种抗扩散被“硬连接”到扩散。据证明，不受约束的E2F活性迫使S期进入并通过p53依赖性和非依赖性机制促进细胞凋亡。在这里，我们证明了腺病毒E1A对E2F的放松调节，Rb丢失或E2F-1表达的增强导致胱天蛋白酶原酶通过直接转录机制积累。此外，在p53产生的信号触发caspase激活的情况下，增加的caspase水平会增强细胞死亡。我们的研究结果表明，促有丝分裂的致癌基因参与了一个抑癌网络，该网络在多个层面发挥作用，有效诱导细胞死亡。重要的是，这项工作提供了细胞周期进程如何与凋亡机制耦合的解释。基因组不稳定性和非整倍性是人类肿瘤的共同特征。尽管认为非整倍性在大多数情况下是由有丝分裂检查点的缺陷引起的，但检查点组件中功能突变的丧失却非常罕见。在这项研究中，我们还表明，有丝分裂检查点蛋白Mad2受E2F转录因子调控，因此，在具有Rb途径缺陷的细胞的整个细胞周期中均不适当表达。正常细胞中Rb途径病变的产生会产生异常的Mad2表达，并与导致多倍体的检查点缺陷相关。仅通过强制Mad2的表达就可以概括这些相同的缺陷。一致地，Mad2诱导的表达加速了Eμ-myc淋巴瘤小鼠模型的肿瘤发生。综上所述，这些结果表明非整倍性是细胞周期控制缺陷的副产物，该缺陷同时危害纺锤体检查点。这项研究提供了一种新模型来解释非整倍性在人类癌症中的出现。

著录项

  • 作者

    Nahle, Zaher.;

  • 作者单位

    State University of New York at Stony Brook.;

  • 授予单位 State University of New York at Stony Brook.;
  • 学科 Biology Cell.; Health Sciences Oncology.; Biology Molecular.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 181 p.
  • 总页数 181
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;肿瘤学;分子遗传学;
  • 关键词

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