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Regulation of the Tumor Suppresser p53 and Survivin by Ras and Ral GTPases: Implications for Malignant Transformation.

机译：Ras和Ral GTP酶对肿瘤抑制因子p53和Survivin的调节：对恶性转化的影响。

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摘要

Although the critical role of the small GTPases Ras and Ral in oncogenesis has been well documented, much remains to be investigated about the molecular mechanism by which these GTPases regulate malignant transformation. The work under this thesis made two major contributions to this field. The first is the discovery that K-Ras, RalA and/or RalB are required for the maintenance of the high levels of the anti-apoptotic protein survivin in some human cancer cells, and the second is the demonstration that down regulation of K-Ras, RalA and/or RalB, but not Raf-1 or Akt1/2, stabilizes the tumor suppressor p53 and reactivates it to inhibit malignant transformation in human cancer cells with mutant K-Ras and wild type p53. Here we found that depletion of K-Ras leads to decreased survivin levels in human cancer cells that harbor mutant K-Ras but not those with wild type Ras. The mechanism by which this occurs involves ubiquitination and subsequent proteasome-mediated degradation of survivin. The presence of mutant K-Ras alone was not sufficient to predict the effects of RalA/B depletion on survivin levels. Indeed, depletion of RalA and/or RalB reduces survivin levels in human cancer cells with wild type p53 and mutant K-Ras, but not in those with mutant p53 and/or wild type K-Ras. The functional relevance of these findings to malignant transformation was further supported by the demonstration that compromising the expression of survivin by siRNA leads to reduction of mutant K-Ras-driven invasion and anchorage-independent growth. Furthermore, in this thesis, we have discovered that down regulation of K-Ras, RalA and/or RalB using siRNA leads to increased levels of functional p53 that is capable of regulating its target genes. The mechanism by which depleting K-Ras, RalA and RalB increases the levels of p53 involves an increase in the half-life of the p53 protein concurrent with an increase in the phosphorylation of serine-15 of p53, a marker of p53 stability. Finally, we demonstrated that depletion of K-Ras, RalA and/or RalB interferes with cell cycle progression, anchorage-independent growth and invasion in a p53-dependent manner. In summary, the studies suggest that mutant K-Ras contributes to the maintenance of the aberrantly-high survivin levels by regulating its stability, and that the ability of mutant K-Ras to induce malignant transformation is, at least in part, dependent of these high levels of survivin. The work of this thesis also suggests that the expression of K-Ras, RalA and/or RalB proteins is critical to maintain low levels of p53, and that down regulation of these GTPases reactivates p53 by significantly enhancing its stability, and this contributes to suppression of malignant transformation.
机译：尽管小GTPases Ras和Ral在致癌作用中的关键作用已得到充分证明，但有关这些GTPases调节恶性转化的分子机制尚有很多研究要做。本论文的工作为该领域做出了两个主要贡献。第一个发现是维持某些人类癌细胞中高水平的抗凋亡蛋白survivin所必需的K-Ras，RalA和/或RalB，第二个是证明K-Ras的下调RalA和/或RalB，而不是Raf-1或Akt1 / 2，可以稳定肿瘤抑制因子p53并使其重新激活，从而抑制具有突变K-Ras和野生型p53的人类癌细胞的恶性转化。在这里，我们发现K-Ras的消耗导致人类癌细胞中Survivin水平降低，而人类癌细胞中却含有突变型K-Ras，而野生型Ras则没有。发生这种情况的机制涉及泛素化和随后的蛋白酶体介导的survivin降解。单独存在突变K-Ras不足以预测RalA / B耗竭对生存素水平的影响。实际上，RalA和/或RalB的消耗降低了具有野生型p53和突变型K-Ras的人类癌细胞中存活蛋白的水平，但没有降低了具有突变型p53和/或野生型K-Ras的人类癌细胞中的生存素水平。这些发现与恶性转化的功能相关性得到了进一步的证实，即通过siRNA破坏survivin的表达会导致突变K-Ras驱动的侵袭和锚定非依赖性生长减少。此外，在本论文中，我们发现使用siRNA下调K-Ras，RalA和/或RalB会导致能够调节其靶基因的功能性p53水平升高。耗尽K-Ras，RalA和RalB增加p53水平的机制涉及p53蛋白半衰期的增加，同时p53的丝氨酸-15的磷酸化的增加，p53的稳定性是p53的标志。最后，我们证明了K-Ras，RalA和/或RalB的耗竭以p53依赖性方式干扰细胞周期进程，锚定非依赖性生长和侵袭。总之，研究表明突变体K-Ras通过调节其稳定性有助于维持异常高的survivin水平，并且突变体K-Ras诱导恶性转化的能力至少部分取决于这些。高水平的survivin。本论文的工作还表明，K-Ras，RalA和/或RalB蛋白的表达对于维持低水平的p53至关重要，并且这些GTPases的下调会通过显着增强其稳定性来重新激活p53，这有助于抑制恶变。

著录项

  • 作者

    Tecleab, Awet G.;

  • 作者单位

    University of South Florida.;

  • 授予单位 University of South Florida.;
  • 学科 Health Sciences Medicine and Surgery.;Health Sciences Oncology.;Biology Molecular.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2013
  • 页码 149 p.
  • 总页数 149
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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