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首页> 外文学位 >Stathmin Depletion from Cells Lacking p53 Leads to Delayed Cell Cycle Progression and Apoptosis Due to Increased Microtubule Stability.
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Stathmin Depletion from Cells Lacking p53 Leads to Delayed Cell Cycle Progression and Apoptosis Due to Increased Microtubule Stability.

机译：缺乏p53的细胞中的stathmin耗竭会导致细胞周期进程的延迟和细胞凋亡，这归因于微管稳定性的提高。

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摘要

Control of cell proliferation is greatly diminished in cancer cells. In order to understand how to prevent the uncontrolled proliferation of cancer cells, it is first important to understand how cells normally control proliferation. Stathmin, a microtubule regulatory protein, is over-expressed in many cancers and required for survival of several cancer lines. In a study of breast cancer cell lines, Alli et al. (Oncogene. 26:1003--12) proposed that stathmin is required for survival of cells lacking p53, but this hypothesis was not tested directly. Here we tested their hypothesis by examining cell survival in cells depleted of stathmin, p53 or both proteins. Comparing HCT116 colon cancer cell lines differing in TP53 genotype, stathmin depletion resulted in significant cell cycle delay and death only in cells lacking p53. As a second experimental system, we compared the effects of stathmin depletion from HeLa cells, which normally lack detectable levels of p53 due to expression of the HPV E6 protein. Stathmin depletion caused a large percentage of HeLa cells to both delay and die via apoptosis. Restoring p53, by depletion of HPV E6, rescued HeLa cells from stathmin-depletion induced delay and death. The stathmin-dependent survival of cells lacking p53 was not confined to cancerous cells because both proteins were required for survival of normal human fibroblasts.;Although, both p53 and stathmin must be lacking to lead to a G2 cell cycle delay, it is still unclear as to why we see this synergy. We hypothesize that stathmin depletion relays a signal via stabilization of the microtubule cytoskeleton, specifically in cells lacking p53. Alternatively, stathmin could have a function separate from its microtubule regulatory activity, and loss of this additional function could lead to cell cycle delay. As a test of our hypothesis, we examined whether microtubule stability is greatest in cells lacking both stathmin and p53. Results showed that HeLa cells depleted of both stathmin and p53 showed a large increase in acetylated microtubules (a marker of microtubule stability) and the rate of microtubule nucleation. Restoring p53 in these cells reduces both the amount of acetylated microtubules and the microtubule nucleation rate in stathmin depleted cells. To further test the link between stathmin depletion in cells lacking p53 and microtubules, the microtubule network was manipulated by either complete depolymerization, with nocodazole, or by restoring the microtubule network to normal levels by over-expressing stathmin truncations that affect the microtubule array (stathmin Delta101-149). Both of these treatments allowed cells to escape the G2 delay, while over-expression of a stathmin truncation that does not affect the microtubule array (stathmin Delta5-25) did not affect the G2 delay.;Our results demonstrate that stathmin is required for cell survival in cells lacking p53, suggesting that stathmin depletion could be used therapeutically to induce a G2 cell cycle delay and apoptosis in tumors without functional p53. Our results also indicate that the interphase microtubule cytoskeleton is a novel target for control of cell proliferation, particularly for the greater than 50% of human cancers that lack p53 because of either inactivating mutations or viral infection. Together the results described in this dissertation could lead to new methods to treat and kill cancer cells that specifically lack p53, while leaving healthy cells relatively unaffected.
机译：在癌细胞中，细胞增殖的控制大大降低了。为了了解如何防止癌细胞的不受控制的增殖，首先重要的是要了解细胞如何正常控制增殖。 Stathmin是一种微管调节蛋白，在许多癌症中均过表达，是多种癌症细胞存活所必需的。在对乳腺癌细胞系的研究中，Alli等人。 （Oncogene。26：1003--12）提出，stathmin是缺乏p53的细胞存活所必需的，但是这一假设没有得到直接检验。在这里，我们通过检查在耗尽stathmin，p53或两种蛋白质的细胞中的细胞存活率来检验它们的假设。比较TP53基因型不同的HCT116结肠癌细胞系，stathmin耗竭仅在缺乏p53的细胞中导致明显的细胞周期延迟和死亡。作为第二个实验系统，我们比较了HeLa细胞中stathmin消耗的影响，该细胞通常由于HPV E6蛋白的表达而缺乏可检测的p53水平。 Stathmin耗竭导致大量HeLa细胞延迟凋亡并通过凋亡而死亡。通过清除HPV E6来恢复p53，可以从Heathmin耗尽引起的延迟和死亡中拯救HeLa细胞。缺少p53的细胞的依赖于stathmin的细胞的存活并不局限于癌细胞，因为这两种蛋白质都是正常人成纤维细胞生存所必需的。尽管p53和stathmin都必须缺乏导致G2细胞周期延迟的作用，但目前尚不清楚关于为什么我们看到这种协同作用。我们假设，stathmin耗竭通过稳定微管细胞骨架传递信号，特别是在缺乏p53的细胞中。另外，stathmin可能具有与其微管调节活性不同的功能，并且丧失该附加功能可能导致细胞周期延迟。作为我们假设的检验，我们检查了在缺乏stathmin和p53的细胞中微管稳定性是否最大。结果显示，耗尽了stathmin和p53的HeLa细胞显示乙酰化微管（微管稳定性的标志物）和微管成核速率大大增加。在这些细胞中恢复p53既可以减少乙酰基微管的乙酰化微管的数量，也可以减少其细胞内的微管成核率。为了进一步测试缺乏p53的细胞中的stathmin耗竭与微管之间的联系，可通过用nocodazole完全解聚或通过过表达影响微管阵列的stathmin截短将其恢复至正常水平来操纵微管网络（stathmin Delta101-149）。这两种处理均使细胞逃避了G2延迟，而不会影响微管阵列的stathmin截短（stathmin Delta5-25）的过表达并不影响G2延迟。缺乏p53的细胞存活率高，提示在没有功能性p53的情况下，stathmin耗竭可用于治疗性G2细胞周期延迟和细胞凋亡。我们的结果还表明，相间微管细胞骨架是控制细胞增殖的新靶标，尤其是对于超过50％的因失活突变或病毒感染而缺乏p53的人类癌症。总之，本文描述的结果可能会导致治疗和杀死特异性缺乏p53的癌细胞的新方法，而使健康细胞相对不受影响。

著录项

  • 作者

    Carney, Bruce K.;

  • 作者单位

    Lehigh University.;

  • 授予单位 Lehigh University.;
  • 学科 Biology Cell.;Biology Molecular.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 127 p.
  • 总页数 127
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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