DEATH RECEPTORS AND ANOIKIS

死亡受体和失巢凋亡

• 批准号: 6595007
• 负责人: Steven Miles Frisch
• 金额: $ 16.84万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-28 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6595007
• 关键词: CD95 molecule; apoptosis; cadherins; cell adhesion; cell line; confocal scanning microscopy; cysteine endopeptidases; cytokine receptors; enzyme activity; integrins; keratin; northern blottings; polymerase chain reaction; tumor necrosis factor alpha; western blottings

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.

描述：（申请人的描述）锚定依赖性是其中之一 体内肿瘤细胞恶性肿瘤的最佳体外相关性。几年前 我们的实验室发现，正常的上皮细胞会凋亡 丢失了适当的整联蛋白介导的矩阵触点（“ Anoikis”）， 重新定义上皮锚定依赖性。本研究将重点放在 阐明了一种新的机制，死亡受体（例如，TNFR1和FAS） 调节Anoikis，锚定依赖性，并通过延伸为肿瘤细胞 恶性。 在几种肿瘤中观察到死亡受体相关蛋白的改变 细胞系统，表明它们在人类癌症中的重要性。 但是，他们 目前尚不清楚这方面的具体作用。 最近，我们发现了 证据表明，死亡受体可能参与启动Anoikis。全面的， 死亡受体的作用及其在Anoikis中的激活机制，以及 这些机制如何受到癌基因的调节，在此中将检查 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，就TNFR1聚类而言和 TNFR1-TRADD关联）在从细胞外基质中分离的细胞中？ 如果是这样， 做已知会调节厌氧菌的信号分子（CD2-FAK，激活 RAS，AKT或C-SRC）会影响受体激活？ 其次，死亡受体吗 Anoikis的激活是独立于死亡配体发生的吗？ （例如，a 细胞骨架隔离与释放机制或通过死亡的修饰 受体信号成分）或由于从头产生而发生 死亡配体？ （例如，翻译上调或蛋白水解 加工）。 第三，钙粘蛋白 - 钙蛋白复合物在该中的作用是什么 对Anoikis的调节？ 这些复合物可以调节死亡受体 激活？ 总而言之，该项目将建立基本参数 剥夺了正常基质相互作用的细胞中死亡受体的激活。 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Anoikis。预计这些研究将 揭示了肿瘤细胞在Anoikis和 这些缺陷如何通过基因治疗或药物来补偿。