• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Mechanisms of mitochondria-mediated apoptosis induced by cytotoxic stress.
【24h】

Mechanisms of mitochondria-mediated apoptosis induced by cytotoxic stress.

机译：细胞毒性应激诱导线粒体介导的细胞凋亡机制。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Defects within the apoptotic pathway are thought to contribute to tumorigenesis and therapeutic resistance. Most cytotoxic anti-cancer drugs are thought to activate the mitochondria-mediated apoptotic pathway; however, the precise mechanistic details remain unclear and, in some instances, controversial. The prevailing view of mitochondria-mediated apoptosis is that the process occurs through a series of events that are orchestrated in a linear step-wise fashion. From this perspective, initiating events include the activation of a BH3-only family member which then activates Bax and/or Bak resulting in their homo-oligomerization and pore formation spanning the outer mitochondrial membrane to induce mitochondrial outer membrane permeabilization (MOMP). Subsequently, cytochrome c and other pro-apoptotic factors are released from the intermembrane space of the mitochondria into the cytosol through this pore. Cytosolic cytochrome c interacts with Apoptotic protease activating factor-1 (Apaf-1) and initiator caspase-9 where this complex serves as the activating platform for initiator caspase-9. Active caspase-9 then activates downstream effector caspase-3 and -7, which produce the biochemical and morphological features associated with apoptosis.;For my dissertation research, I have investigated the underlying molecular requirements necessary for mitochondria-mediated apoptosis induced by a DNA topoisomerase II inhibitor, a novel heat shock protein 90 (Hsp90) inhibitor, and elevated temperature in Jurkat T-lymphocytes. Combined, the data suggest that different cytotoxic stressors use similar as well as distinct mechanisms to execute mitochondria-mediated apoptosis. In addition, the data provide new insights into the mechanistic details utilized by these three different stressors, which may prove useful for future drug design and therapeutic approaches.;In the first Specific Aim, I investigated the molecular requirements necessary for mitochondria-mediated apoptosis in response to the DNAdamaging drug etoposide. The data suggest that the BH3-only family member Bid is important during DNA-damage induced apoptosis where it functions to facilitate MOMP. These studies also found that the active form of the protein, tBid, is generated downstream of initiator caspase-9 activation by executioner caspase-3 and/or -7. Taken together, these data suggest that effector caspases, Bid, and mitochondria forge an amplification loop to irreversibly commit a cell to apoptosis.;The antiproliferative effects of a novel C-terminal inhibitor of Hsp90, designated KU135, were characterized in the second Specific Aim. This study compared the effects of an N-terminal Hsp90 inhibitor, 17-AAG, to the effects of the C-terminal Hsp90 inhibitor, KU135. KU135 was found to have more potent antiproliferative effects than 17-AAG, and KU135 activated the mitochondria-mediated apoptotic pathway, whereas 17-AAG was primarily cytostatic. Finally, 17-AAG caused robust induction of the cytoprotective proteins Hsp90 and Hsp70 which could account for its lack of an apoptotic response.;The molecular requirements for heat-induced apoptosis were examined in the third Specific Aim. The data showed that heat-induced apoptosis is a mitochondria-mediated event and that caspase-9, and not caspase-2, is the most apically activated caspase. The BH3-only protein, Bid, was found to be important during heat-induced apoptosis where it was needed to facilitate MOMP. However, we found that tBid was generated downstream of caspase-9 suggesting that it may function to promote cytochrome c release during this process as part of a feed forward amplification loop.
机译：凋亡途径内的缺陷被认为有助于肿瘤发生和治疗抗性。大多数细胞毒性抗癌药物被认为可以激活线粒体介导的凋亡途径。但是，确切的机械细节仍然不清楚，在某些情况下还存在争议。线粒体介导的细胞凋亡的普遍观点是，该过程通过一系列以线性逐步方式协调的事件发生。从这个角度来看，引发事件包括仅BH3家族成员的激活，然后激活Bax和/或Bak导致它们的均聚和跨线粒体外膜的孔形成，从而诱导线粒体外膜通透性（MOMP）。随后，细胞色素c和其他促凋亡因子从线粒体的膜间空间通过该孔释放到细胞质中。胞质细胞色素c与凋亡蛋白酶激活因子1（Apaf-1）和启动子caspase-9相互作用，其中该复合物充当启动子caspase-9的激活平台。活性caspase-9然后激活下游效应子caspase-3和-7，产生与凋亡相关的生化和形态学特征。；在我的论文研究中，我研究了线粒体介导的DNA拓扑异构酶介导的细胞凋亡的潜在分子需求。 II抑制剂，一种新型的热激蛋白90（Hsp90）抑制剂，Jurkat T淋巴细胞的温度升高。结合起来，数据表明不同的细胞毒性应激源使用类似以及不同的机制来执行线粒体介导的细胞凋亡。此外，这些数据为这三种不同的应激源所利用的机制细节提供了新的见解，可能被证明对未来的药物设计和治疗方法很有用。在第一个具体目标中，我研究了线粒体介导的细胞凋亡所必需的分子需求。对DNA破坏药物依托泊苷的反应。数据表明，仅BH3家族成员Bid在DNA损伤诱导的凋亡过程中很重要，在凋亡过程中它有助于促进MOMP。这些研究还发现，蛋白质的活性形式tBid是由执行者caspase-3和/或-7在启动子caspase-9激活的下游产生的。综上所述，这些数据表明效应子胱天蛋白酶，Bid和线粒体形成了一个扩增环，使细胞不可逆转地发生凋亡。第二个特异性目的是表征新型Hsp90 C末端抑制剂KU135的抗增殖作用。 。这项研究比较了N末端Hsp90抑制剂17-AAG和C末端Hsp90抑制剂KU135的作用。发现KU135比17-AAG具有更强的抗增殖作用，并且KU135激活了线粒体介导的凋亡途径，而17-AAG主要具有抑制细胞生长的作用。最终，17-AAG强烈诱导了细胞保护蛋白Hsp90和Hsp70的表达，这可以解释其缺乏凋亡反应。在第三个“特定目的”中研究了热诱导细胞凋亡的分子要求。数据表明，热诱导的细胞凋亡是线粒体介导的事件，而caspase-9而不是caspase-2是最顶端活化的caspase。发现仅BH3的蛋白Bid在热诱导的细胞凋亡过程中很重要，在该过程中，它需要促进MOMP。但是，我们发现tBid在caspase-9的下游产生，表明它可能在此过程中起到促进细胞色素c释放的作用，这是前馈扩增环的一部分。

著录项

  • 作者

    Shelton, Shary N.;

  • 作者单位

    University of Kansas.;

  • 授予单位 University of Kansas.;
  • 学科 Biology Molecular.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 211 p.
  • 总页数 211
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号