Regulation of Apoptosis by Mitochondrial Septins, ARTS

线粒体脓毒症对细胞凋亡的调节，ARTS

• 批准号: 6540864
• 负责人: HERMANN STELLER
• 金额: $ 4.03万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540864
• 关键词: Drosophilidae; Mammalia; apoptosis; arthropod genetics; biological signal transduction; cell cycle proteins; cysteine endopeptidases; cytochrome c; enzyme activity; gene mutation; mitochondria; molecular biology; molecular cloning; mutant; protein structure function; tissue /cell culture; transforming growth factors

Apoptosis is a morphologically distinct from of programmed cell death that plays important roles in development, tissue homeostasis and a wide variety of diseases, including cancer, AIDS, stroke, myopathies and various neurodegenerative disorders. Mitochondria have a key function for; sensing and propagating cell death signals. For example, the release of cytochrome c from mitochondria into the cytoplasm is thought to be a critical step for activating the cell death program. A new mitochondrial protein, termed-ARTS (Apoptosis Related protein in the TGF-beta Signaling pathway), appears to mediate the induction of apoptosis in mammalian cells in response to several distinct death-inducing stimuli. ARTS is a novel septin protein family member that translocates; from mitochondria to the nucleus at the onset of apoptosis. Furthermore, a Drosophila homolog of ARTS, encoded by the peanut locus, is required for the induction of cell death by the pro-apoptotic genes reaper, hid and grim in this organism. The overall objective of the proposed research is to use an integrated approach that combines Drosophila genetics and molecular biology with mammalian cell culture experiments to gain insight into the mechanism by which ARTS induces apoptosis. We will address the following specific questions: 1. How conserved is the pro-apoptotic function of human ARTS and Drosophila PEANUT? 2. What is the role of ARTS for cell killing by the pro-apoptotic proteins Reaper, Hid and Grim in mammalian cells? 3. Where in the cell does ARTS act to induce apoptosis? 4. Are there functional and biochemical interactions between ARTS/peanut with IAPS (inhibitor of apoptosis proteins) and Sina/Siah proteins? This work should significantly advance our understanding of how apoptosis is regulated, and how this process can be manipulated for therapeutic purposes.

凋亡在形态学上与程序性细胞死亡的不同，在发育，组织稳态和多种疾病中起着重要作用，包括癌症，艾滋病，中风，肌病和各种神经退行性疾病。线粒体具有关键功能；传感和传播细胞死亡信号。例如，将细胞色素C从线粒体释放到细胞质被认为是激活细胞死亡程序的关键步骤。一种新的线粒体蛋白，称为ARTS（TGF-β信号通路中的凋亡相关蛋白），似乎可以介导哺乳动物细胞中凋亡的诱导，以响应几种不同的诱导死亡刺激。艺术是一种新颖的Septin蛋白家族成员，可易位。从线粒体到细胞凋亡开始时的细胞核。此外，由花生基因座编码的果蝇同源物是该生物体中促凋亡基因的收割机，HID和Grim诱导细胞死亡所必需的。拟议研究的总体目标是使用一种综合方法，该方法将果蝇遗传学和分子生物学与哺乳动物细胞培养实验相结合，以深入了解艺术诱导凋亡的机制。我们将解决以下特定问题：1。人类艺术和果蝇花生的促凋亡功能如何保守？ 2。哺乳动物细胞中，促凋亡蛋白，HID和Grim杀死细胞的作用是什么？ 3。在细胞中，艺术在哪里诱导凋亡？ 4。艺术/花生与IAP（凋亡蛋白抑制剂）和Sina/Siah蛋白之间是否存在功能和生化相互作用？这项工作应该大大提高我们对如何调节细胞凋亡的理解，以及如何用于治疗目的进行此过程。