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.

细胞凋亡在形态学上不同于程序性细胞死亡，其在发育、组织稳态和多种疾病（包括癌症、AIDS、中风、肌病和各种神经退行性疾病）中起重要作用。线粒体具有感知和传播细胞死亡信号的关键功能。例如，细胞色素c从线粒体释放到细胞质中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），似乎介导了哺乳动物细胞对几种不同的死亡诱导刺激的凋亡诱导。ARTS是一种新的septin蛋白家族成员，在细胞凋亡开始时从线粒体易位到细胞核。此外，由花生基因座编码的ARTS的果蝇同源物是该生物体中促凋亡基因reaper、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，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ARTS诱导细胞凋亡的机制。我们将讨论以下具体问题：1。人类ARTS和果蝇花生的促凋亡功能有多保守？2. ARTS在哺乳动物细胞中通过促凋亡蛋白Reaper、Hid和Grim杀死细胞中的作用是什么？3. ARTS在细胞的什么部位起诱导凋亡的作用？4. ARTS/花生与凋亡抑制蛋白（IAPS）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细胞凋亡是如何调节的理解，以及如何操纵这一过程以达到治疗目的。