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（由申请人提供）：细胞死亡的正确执行可确保正常的生物过程，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受调节形式。细胞凋亡受损不仅是癌症发展的核心，而且还使肿瘤对细胞毒治疗产生耐药性。因此，进一步阐明凋亡信号传导框架不仅有助于了解癌细胞如何逃避凋亡检查点，而且有助于开发合理设计的靶向癌症治疗。 BCL-2 家族蛋白在线粒体上控制细胞死亡与生存的决定，可分为三个亚家族：（1）多域抗凋亡 BCL-2、BCL-XL 和 MCL-1； (2)多结构域促凋亡BAX和BAK； (3) 仅促凋亡 BH3 分子 (BH3s)。 BH3 传递上游凋亡信号，通过激活 BAX/BAK 或失活 BCL-2/BCL-XL/MCL-1 来促进细胞凋亡。遗传功能丧失研究揭示了上游“激活剂”BH3 和下游 BAX/BAK 在激活线粒体依赖性细胞凋亡中的重要轴。响应细胞凋亡信号，“激活剂”BH3（包括 BID、BIM 和 PUMA）触发 BAX 和 BAK 的同源寡聚化，使线粒体透化，导致细胞色素 c 流出至胞质溶胶以激活 caspase。我们最近发现了 BH3 激活 BAX/BAK 依赖性线粒体透化作用的新机制。我们建议阐明这种新机制，并根据 BH3 启动细胞死亡的机制对其进行重新分类。 BH3 激活 BAX/BAK 不仅会触发 APAF-1 介导的 caspase 激活，还会引发 caspase 依赖性细胞死亡。这种新型细胞死亡形式的进一步表征为未来开发针对具有缺陷的半胱天冬酶激活的癌细胞的抗癌疗法带来了希望。我们还在研究 BAX 和 BAK 是否存在于不同的蛋白质复合物中，以差异调节 caspase 依赖性和非依赖性细胞死亡程序。总的来说，我们的目标是建立一个全面的促凋亡 BCl-2 信号网络来激活线粒体依赖性细胞死亡程序，这为治疗干预提供了共同点。