SIGNALING OF APOPTOSIS IN CANCER

癌症中细胞凋亡的信号

• 批准号: 6173269
• 负责人: Glenn D. Rosen
• 金额: $ 20.21万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173269
• 关键词: apoptosis; biological signal transduction; cell line; chemical cleavage; cysteine endopeptidases; cytolysis; dexamethasone; enzyme mechanism; guanosinetriphosphatase activating protein; interferon gamma; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; neoplastic cell; nuclear factor kappa beta; transcription factor; transfection; tumor necrosis factor alpha

DESCRIPTION: Recent studies have demonstrated that tumor cells are more sensitive than normal cells to an apoptotic signal induced by a member of the tumor necrosis factor (TNF) family called TNF-related apoptosis- inducing ligand (TRAIL) also known as Apo2L. The applicant has made several interesting observations, including: (i) interferon gamma (INF- gamma) sensitizes A549, HT1090 and ME180 cancer cells to Apo2L-induced apoptosis; (ii) expression of transcription factor, INF regulatory factor (IFR-1), is also induced in these cells by INF-gamma; (iii) activation of Apo2L pathway activates specific caspases that induces cleavage of p120/Ras GTPase; and (iv) dexamethasone is a potent inhibitor of Apo2L-induced cell death. The goal of this application is to investigate the TRAIL/Apo2L pathway in tumor cells and define parts of the TRAIL/Apo2L signaling pathway that may lead to a better understanding the mechanisms underlying how cell killing of tumor cells occurs. Three Specific Aims are proposed: (I) to examine the mechanisms by which IRF-1 regulates the sensitization of tumor cells by IFN-gamma to the Apo2L-induced apoptosis; (II) to characterize the role of caspase-mediated cleavage of ras GAP during Apo2L-induced apoptosis; and (III) to determine the targets of dexamethasone's actions in the Apo2L pathway.

描述：最近的研究表明肿瘤细胞更多 对由成员诱导的凋亡信号敏感的细胞敏感 称为TNF相关凋亡的肿瘤坏死因子（TNF）家族 诱导配体（小径）也称为apo2l。申请人做了 几个有趣的观察结果，包括：（i）干扰素伽玛（Inf- 伽玛）将A549，HT1090和ME180癌细胞敏感到APO2L诱导的 凋亡； （ii）转录因子的表达，INF调节 因子（IFR-1）在这些细胞中也通过inf-gamma诱导。 （iii） APO2L途径的激活激活诱导的特定胱天蛋白酶 P120/RAS GTPase的切割； （iv）地塞米松是一个有效的 APO2L诱导的细胞死亡的抑制剂。 该应用的目的是 调查肿瘤细胞中的TRAIL/APO2L途径并定义部分 TRAIL/APO2L信号通路可能会导致更好 了解肿瘤细胞细胞杀死细胞的基础机制 发生。 提出了三个具体目标：（i）检查 IRF-1调节肿瘤细胞敏化的机制 ifn-gamma to apo2l诱导的凋亡； （ii）表征角色 caspase介导的RAS间隙的切割过程中apo2l诱导的凋亡； （iii）确定地塞米松在 APO2L途径。