SIGNALING OF APOPTOSIS IN CANCER

描述：最近的研究表明，肿瘤细胞比 比正常细胞对成员诱导的凋亡信号敏感 肿瘤坏死因子家族的成员，称为肿瘤坏死因子相关的细胞凋亡- 诱导配体(TRAIL)，也称为载脂蛋白2L。申请人已作出 几个有趣的观察结果，包括：(I)干扰素- Gamma)增敏A549、HT1090和ME180癌细胞对载脂蛋白2L的诱导 细胞凋亡；(Ii)转录因子的表达，INF调节 干扰素-γ也能在这些细胞中诱导因子(IFR-1)；(Iii) Apo2L途径的激活激活了特定的caspase，从而诱导 对p120/RAS GTP酶的切割；以及(Iv)地塞米松是一种有效的 载脂蛋白2L诱导细胞死亡的抑制剂。此应用程序的目标是 研究肿瘤细胞中TRAIL/Apo2L通路并确定部分 TRAIL/Apo2L信号通路可能导致更好的 了解细胞如何杀伤肿瘤细胞的机制 发生。提出了三个具体目标：(I)审查 IRF-1调节肿瘤细胞增敏的机制 干扰素-γ对载脂蛋白2L诱导的细胞凋亡的影响 在载脂蛋白2L诱导的细胞凋亡过程中caspase介导的ras间隙的裂解； 以及(Iii)确定地塞米松在 载脂蛋白2L途径。

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.