Apoptotic Network Integrated at the Mitochondrion

线粒体整合的凋亡网络

• 批准号: 7268258
• 负责人: EMILY H CHENG
• 金额: $ 28.91万
• 依托单位: WASHINGTON UNIVERSITY
• 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 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7268258
• 关键词: Address; Apoptosis; Apoptotic; BAK1 gene; BAX gene; BCL-2 Protein; BCL2L11 gene; Bax protein; Biochemical; Caspase; Cell Death; Cells; Cessation of life; Complex; Cytotoxic Chemotherapy; Development; Family; Genetic; Genetic Models; Genome; Goals; Homeostasis; Impairment; Individual; Maintenance; Malignant Neoplasms; Mammals; Maps; Mediating; Mitochondria; Molecular Profiling; Organism; Pathway interactions; Play; Protein Family; Proteins; Refractory; Regulation; Role; Signal Transduction; Therapeutic; Translating; VDAC2 gene; base; cancer cell; cancer therapy; cytochrome c; killings; member; mitochondrial dysfunction; novel; prevent; programs; release factor; small molecule; tumor

DESCRIPTION (provided by applicant): Apoptosis plays an essential role in the development and maintenance of homeostasis within multicellular organisms. Impairment of apoptosis is not only central to cancer development but also renders tumors refractory to cytotoxic therapy. The BCL-2 family proteins, consisting of both anti-apoptotic and proapoptotic members, constitute a crucial checkpoint in the cell death pathway. Our prior studies have helped delineate the core apoptotic pathway in mammals. The BH3-only molecules activate multidomain proapoptotic BAX and BAK to releases cytochrome c for caspase activation and initiate caspase-independent mitochondrial dysfunction. Conversely, anti-apoptotic BCL-2/BCL-XL sequesters BH3-only molecules into inert complexes, thus preventing the activation of BAX and BAK. Genetic studies revealed that absence of proapoptotic BAX and BAK creates a profound block in apoptosis triggered by diverse death signals including cancer therapeutics. Thus, activation of a multidomain member, BAX or BAK, appears to be an obligate gateway to the mitochondrion-mediated cell death program. However, it remains unclear whether all the BH3-only molecules are capable of activating BAX and BAK, how the BH3-only molecules activate BAX and BAK, and which BH3-only molecule and how it is activated by each specific death signal to initiate the apoptotic signaling cascade. Emerging evidence suggests that anti-apoptotic BCL-2 members are selectively inactivated by different BH3-only molecules, but detailed functional map of individual BH3-only molecules in antagonizing anti-apoptotic BCL-2 members is still missing. Moreover, it remains debated whether anti- apoptotic BCL-2 members inhibit apoptosis through direct inhibition of BAX/BAK and/or sequestration of BH3-only molecules. Finally, it is critical to determine how BAX and BAK are kept in check in viable cells. Are they kept in check by anti-apoptotic BCL-2 members or by other associated proteins such as VDAC2? To address these questions, we propose to characterize the BH3-only molecules, assign and identify individual BH3-only molecules to integrate apoptotic signaling cascades and mitochondrion-dependent death program, dissect the mechanisms by which BH3-only molecules activate BAX and BAK, and establish a functional network of differential regulation among various BCL-2 subfamilies. Our ultimate goal is to translate the mechanisms governing death/survival decision by BCL-2 family into anti-cancer strategies.

描述（由申请人提供）：细胞凋亡在多细胞生物体内稳态的发展和维持中起着至关重要的作用。细胞凋亡的损害不仅是癌症发展的核心，而且使肿瘤对细胞毒性治疗难以耐受。BCL-2家族蛋白包括抗凋亡和促凋亡成员，在细胞死亡途径中构成了一个重要的检查点。我们之前的研究已经帮助描述了哺乳动物的核心凋亡途径。BH3-only分子激活多结构域促凋亡BAX和BAK，释放细胞色素c激活caspase，引发caspase非依赖性线粒体功能障碍。相反，抗凋亡的BCL-2/BCL-XL将BH3-only分子隔离成惰性复合物，从而阻止BAX和BAK的活化。遗传学研究表明，缺乏促凋亡的BAX和BAK会对包括癌症治疗在内的多种死亡信号引发的细胞凋亡产生深远的阻碍。因此，多结构域成员BAX或BAK的激活似乎是线粒体介导的细胞死亡程序的必经之路。然而，是否所有的BH3-only分子都能够激活BAX和BAK， BH3-only分子如何激活BAX和BAK，哪些BH3-only分子以及它如何被每个特定的死亡信号激活以启动凋亡信号级联尚不清楚。越来越多的证据表明，抗凋亡BCL-2成员可被不同的BH3-only分子选择性失活，但具体的BH3-only分子在拮抗抗凋亡BCL-2成员中的功能图谱尚不清楚。此外，抗凋亡的BCL-2成员是否通过直接抑制BAX/BAK和/或仅隔离bh3分子来抑制细胞凋亡仍存在争议。最后，确定BAX和BAK如何在活细胞中得到控制是至关重要的。它们是否受到抗凋亡BCL-2成员或其他相关蛋白（如VDAC2）的控制？为了解决这些问题，我们建议表征BH3-only分子，分配和鉴定单个BH3-only分子整合凋亡信号级联和线粒体依赖的死亡程序，剖析BH3-only分子激活BAX和BAK的机制，并建立不同BCL-2亚家族之间差异调节的功能网络。我们的最终目标是将BCL-2家族的死亡/生存决定机制转化为抗癌策略。