Apoptotic Network Integrated at the Mitochondrion

线粒体整合的凋亡网络

• 批准号: 9487176
• 负责人: EMILY H CHENG
• 金额: $ 35.62万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9487176
• 关键词: Adaptor Signaling Protein; Affect; Apoptosis; Apoptotic; BAX gene; BCL1 Oncogene; BCL2 gene; BCL2L11 gene; BIK gene; Biochemical Genetics; Biological Process; Caspase; Categories; Cell Death; Cessation of life; Cytosol; Cytotoxic Chemotherapy; Data; Development; Ensure; Family; Future; Genetic; Genetic study; Goals; Homeostasis; Homo; Human; Impairment; Knowledge; Maintenance; Malignant Neoplasms; Mediating; Membrane; Mitochondria; Modeling; Molecular; Morphology; Necrosis; Neurodegenerative Disorders; Organism; Outer Mitochondrial Membrane; PMAIP1 gene; Pathway interactions; Play; Protein Family; Refractory; Regulation; Role; Signal Transduction; Stimulus; Therapeutic; Therapeutic Intervention; Tumor Suppressor Proteins; Work; anti-cancer therapeutic; apoptotic protease-activating factor 1; base; c-myc Genes; cancer cell; cytochrome c; design; in vivo; loss of function; new therapeutic target; novel; parkin gene/protein; prevent; programs; protein complex; public health relevance; response; targeted cancer therapy; therapeutic target; tumor; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): Proper execution of cell death ensures normal biological processes, and its dysregulation causes human illness, ranging from cancer to neurodegenerative disorders. Apoptosis is a regulated form of cell death. Impairment of apoptosis is not only central to cancer development but also renders tumors refractory to cytotoxic therapy. Hence, further elucidation of the apoptotic signaling framework will not only help understand how cancer cells escape apoptotic checkpoints but also contribute to the development of rationally designed targeted cancer therapy. The BCL-2 family proteins govern cell death-versus-survival decisions at the mitochondria and can be divided into three subfamilies: (1) multidomain antiapoptotic BCL-2, BCL-XL and MCL-1; (2) multidomain proapoptotic BAX and BAK; and (3) proapoptotic BH3-only molecules (BH3s). BH3s relay upstream apoptotic signals to promote apoptosis by either activating BAX/BAK or inactivating BCL-2/BCL-XL/MCL-1. Genetic loss-of-function studies reveal an essential axis of upstream "activator" BH3s and downstream BAX/BAK in activating mitochondrion-dependent apoptosis. In response to apoptotic signals, the "activator" BH3s, including BID, BIM and PUMA, trigger the homo-oligomerization of BAX and BAK to permeabilize mitochondria, leading to the efflux of cytochrome c to the cytosol for caspase activation. We recently discovered a novel mechanism by which BH3s activate BAX/BAK- dependent mitochondrial permeabilization. We propose to elucidate this novel mechanism and reclassify BH3s based on their mechanisms in initiating cell death. Activation of BAX/BAK by BH3s not only triggers APAF-1-mediated caspase activation but also initiates caspase- independent cell death. Further characterization of this novel form of cell death holds promises for the future development of anti-cancer therapeutics that targets cancer cells with defective caspase activation. We are also pursing whether BAX and BAK reside in different protein complexes to differentially regulate caspase-dependent and -independent cell death programs. Overall, our goal is to build a comprehensive proapoptotic BCl-2 signaling network in activating mitochondrion-dependent cell death programs, which offers common ground for therapeutic interventions.

描述(申请人提供)：细胞死亡的正确执行确保了正常的生物过程，其失调会导致人类疾病，从癌症到神经退行性疾病。细胞凋亡是细胞死亡的一种调节形式。细胞凋亡的损害不仅是癌症发展的中心，而且也使肿瘤对细胞毒治疗难以产生作用。因此，进一步阐明凋亡信号框架不仅有助于理解癌细胞如何逃脱凋亡检查点，而且有助于开发合理设计的靶向癌症治疗方法。BCL-2家族蛋白在线粒体上控制细胞的生死决定，可分为三个亚家族：(1)多结构域抗凋亡性BCL-2、BCL-XL和MCL-1；(2)多结构域促凋亡性Bax和BAK；(3)促凋亡性BH3分子(BH3s)。BH3通过激活Bax/BAK或失活BCL-2/BCL-XL/MCL-1，传递上游的凋亡信号来促进细胞凋亡。遗传功能丧失研究揭示了上游的“激活物”BH3s和下游的Bax/BAK在激活线粒体依赖的细胞凋亡中的一个重要轴。Bid、BIM和PUMA等BH3s作为细胞凋亡信号的“激活剂”，通过触发Bax和BAK的同源寡聚作用，使线粒体通透性增强，导致细胞色素c外流到胞浆中，激活caspase。我们最近发现了BH3激活依赖于Bax/BAK的线粒体通透性的新机制。我们建议阐明这一新的机制，并根据它们启动细胞死亡的机制对BH3进行重新分类。BH3S激活Bax/BAK不仅可以激活Apaf-1介导的caspase，还可以启动caspase非依赖的细胞死亡。这种新的细胞死亡形式的进一步表征为以caspase激活缺陷的癌细胞为靶点的抗癌治疗的未来发展提供了希望。我们还在寻找Bax和BAK是否存在于不同的蛋白质复合体中，以不同的方式调控caspase依赖和非依赖的细胞死亡程序。总体而言，我们的目标是建立一个全面的促凋亡bcl2信号网络来激活线粒体依赖的细胞死亡程序，这为治疗干预提供了共同的基础。