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）：凋亡在多细胞生物内体内平衡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，而且还使肿瘤对细胞毒性疗法难治性。 Bcl-2家族蛋白由抗凋亡和促凋亡成员组成，构成了细胞死亡途径中的关键检查点。我们先前的研究帮助描绘了哺乳动物中的核心凋亡途径。仅BH3-仅BH3分子激活多域促凋亡Bax和Bak，以释放细胞色素C进行caspase激活，并启动与caspase无关的线粒体功能障碍。相反，抗凋亡的Bcl-2/Bcl-XL隔离器仅BH3分子进入惰性复合物，从而阻止了Bax和Bak的激活。遗传研究表明，缺乏丙凋亡的Bax和Bak在包括癌症治疗在内的多种死亡信号引起的凋亡中产生了深远的凋亡。因此，多域成员BAX或BAK的激活似乎是通往线粒体介导的细胞死亡程序的强制性门户。但是，尚不清楚所有仅BH3的分子是否能够激活Bax和Bak，仅BH3分子如何激活BAX和BAK，以及哪些BH3分子以及如何通过每个特定死亡信号激活它以启动poptotic信号级联。新兴的证据表明，抗凋亡的Bcl-2成员被不同的仅BH3分子选择性地灭活，但是在拮抗抗凋亡Bcl-2成员中，单个仅BH3的单个仅单个BH3分子的详细功能图仍缺失。此外，它仍然争论抗凋亡BCL-2成员是否通过直接抑制BAX/BAK和/或仅BH3分子抑制凋亡。最后，确定Bax和Bak如何在可行的细胞中保存下来是至关重要的。它们是否由抗凋亡BCL-2成员或其他相关蛋白（例如VDAC2）控制？为了解决这些问题，我们建议表征仅BH3的分子，分配和识别单个仅BH3的分子，以整合凋亡信号传导级联和线粒体依赖性死亡程序，剖析BH3键性分子激活BAX和BAK的机制，并在各种Bak中建立了型号的bak，并建立了一个型号的bak。我们的最终目标是将BCL-2家族死亡/生存决定的机制转化为反癌策略。