DEATH RECEPTORS AND ANOIKIS

描述：(申请人描述)依赖锚地是一种 体内肿瘤细胞恶性程度的最佳体外相关性。几年前， 我们的实验室发现，如果正常的上皮细胞发生凋亡， 适当的整合素介导的基质接触丢失(“失巢细胞”)，这是 重新定义上皮锚定依赖。本研究将重点放在 阐明死亡受体(如TNFR1和Fas)的一种新机制 调节失巢细胞、锚定依赖，进而调节肿瘤细胞 恶毒。 在几种肿瘤中观察到死亡受体相关蛋白的变化 细胞系统，表明它们在人类癌症中的重要性。然而，他们的 在这方面的具体作用目前尚不清楚。最近，我们发现 死亡受体可能参与启动失巢的证据。总的来说， 死亡受体在失巢失巢中的作用及其激活机制 这些机制是如何被癌基因调控的，将在本文中进行研究。 项目。 我们将特别解决以下问题。首先，是死亡 受体本身被激活(即，在TNFR1聚集和 从细胞外基质中分离出来的细胞中的TNFR1-Tradd关联？如果是的话， DO已知的调节失巢凋亡的信号分子(CD2-FAK，激活 RAS、Akt或c-src)影响受体激活？其次，死亡感受器 失巢诱导因子的激活不依赖死亡配体？(例如，通过 细胞骨架隔离与释放机制，或通过修饰死亡 受体信号组件)，或者它是由于从头产生 死亡配体的身份？(例如，翻译上调或蛋白水解物 正在处理)。第三，钙粘附素-连环蛋白复合体在高血压发病中的作用 对失眠的监管？这些复合体能调节死亡受体吗？ 激活？ 总而言之，这个项目将建立 失去正常基质相互作用的细胞中死亡受体的激活。 它还将揭示癌蛋白或细胞黏附的新机制 分子可以调节失巢凋亡。预计这些研究将 揭示肿瘤细胞失巢失巢障碍的新机制 这些缺陷如何通过基因疗法或药物来弥补。

DESCRIPTION: (Applicant's Description) Anchorage-dependence is one of the best in vitro correlates of tumor cell malignancy in vivo. Several years ago, our laboratory discovered that normal epithelial cells undergo apoptosis if appropriate integrin-mediated matrix contacts are lost ("anoikis"), which re-defines epithelial anchorage dependence.The present study will focus on elucidating a novel mechanism by which death receptors (e.g., TNFR1 and FAS) regulate anoikis, anchorage-dependence, and, by extension, tumor cell malignancy. Alterations in death receptor-related proteins are observed in several tumor cell systems, suggesting their importance in human cancer. However, their specific role in this regard is unclear at present. Recently, we have found evidence that death receptors may be involved in initiating anoikis. Overall, the role of death receptors and their mechanism of activation in anoikis, and how these mechanisms are regulated by oncogenes, will be examined in this project. We will address the following questions in particular. First, are the death receptors themselves activated (i.e., in terms of TNFR1 clustering and TNFR1-TRADD association) in cells detached from extracellular matrix? If so, do signaling molecules that are known to regulate anoikis (CD2-FAK, activated ras, Akt or c-src) affect receptor activation? Secondly, does death receptor activation in anoikis occur independently of a death ligand? (e.g., by a cytoskeletal sequestration vs. release mechanism, or by modification of death receptor signaling components) or does it occur due to the de novo production of a death ligand? (e.g., translational upregulatation or proteolytic processing). Thirdly, what is the role of cadherin-catenin complexes in the regulation of anoikis? and can these complexes regulate death receptor activation? In summary, this project will establish the basic parameters underlying the activation of death receptors in cells deprived of normal matrix interactions. It will also reveal novel mechanisms wherein oncoproteins or cell adhesion molecules can regulate anoikis. It is anticipated that these studies will reveal novel mechanisms by which tumor cells become defective in anoikis and how these defects might be compensated by gene therapy or drugs.