DEATH RECEPTORS AND ANOIKIS

描述：（申请人的描述）锚定依赖性是一种 与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，正常上皮细胞发生凋亡， 适当的整联蛋白介导的基质接触丧失（“失巢凋亡”）， 重新定义上皮锚定依赖性。本研究将集中在 阐明了死亡受体（例如，TNFR 1和FAS） 调节失巢凋亡、锚定依赖性，进而调节肿瘤细胞 恶性肿瘤 死亡受体相关蛋白的改变在几种肿瘤中被观察到。 细胞系统，表明它们在人类癌症中的重要性。 但他们的 这方面具体作用目前尚不清楚。 最近，我们发现 死亡受体可能参与了失巢凋亡的发生。总的来说， 死亡受体的作用及其在失巢凋亡中的激活机制， 这些机制是如何调节的癌基因，将在这一研究。 项目 我们将特别讨论以下问题。 首先，死亡 受体本身被激活（即，在TNFR 1聚集方面， TNFR 1-TRADD协会）在细胞脱离细胞外基质？ 如果是这样的话， 已知调节失巢凋亡的信号分子（CD 2-FAK，活化的 ras、Akt或c-src）影响受体活化？ 第二，死亡受体 失巢凋亡中的激活独立于死亡配体发生？ (e.g.,由 细胞骨架螯合与释放机制，或通过死亡的修饰 受体信号传导成分），还是由于从头产生 一个死亡配体 (e.g.,翻译上调或蛋白水解 加工）。 第三，钙粘蛋白-连环蛋白复合物在细胞凋亡中的作用是什么？ 规范失巢凋亡？ 这些复合物能调节死亡受体吗 激活？ 总之，本项目将确定基本参数， 在失去正常基质相互作用的细胞中激活死亡受体。 它还将揭示新的机制，其中癌蛋白或细胞粘附 分子可以调节失巢凋亡。预计这些研究将 揭示了肿瘤细胞在失巢凋亡中变得有缺陷的新机制， 这些缺陷如何通过基因治疗或药物来弥补。

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.