Apoptotic Network Integrated at the Mitochondrion

项目摘要 细胞死亡的正确执行确保了正常的生物过程及其失调 会导致人类疾病，从癌症到神经退行性疾病。细胞凋亡是一种 细胞死亡的调节形式。细胞凋亡受损不仅是癌症发展的中心 但也会使肿瘤对细胞毒治疗难以奏效。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 检查站，但也有助于开发合理设计的靶向癌症 心理治疗。Bcl-2家族蛋白在细胞死亡与存活的决定中起着主导作用。 线粒体可分为三个亚家族：(1)多结构域抗凋亡基因bcl-2， BCL-XL和MCL-1；(2)多结构域促凋亡的Bax和BAK；以及(3)仅促凋亡的BH3 分子(BH3)。BH3s通过传递上游的凋亡信号来促进细胞凋亡 激活Bax/BAK或失活bcl2/bclxl/mcl1。遗传功能丧失研究 揭示上游激活剂BH3s和下游Bax/BAK在激活中的本质轴 线粒体依赖性细胞凋亡。作为对细胞凋亡信号的反应，“激活剂”BH3， 包括BID、BIM和PUMA，触发BAX和BAK的同源齐聚以 使线粒体通透性，导致细胞色素c外流到胞浆中以获得caspase 激活。我们最近发现了一种新的BH3激活Bax/BAK的机制- 依赖线粒体的通透性。我们建议阐明这一新的机制，并 根据BH3在启动细胞死亡中的机制对其进行重新分类。BAX/BAK的激活 BH3s不仅触发Apaf-1介导的caspase激活，而且还启动caspase-1 独立细胞死亡。对这种新的细胞死亡形式的进一步描述是有希望的 针对有缺陷的癌细胞的抗癌治疗药物的未来发展 半胱氨酸酶的激活。我们还在寻找Bax和BAK是否存在于不同的蛋白质中 不同地调节caspase依赖和非依赖细胞死亡程序的复合体。 总体而言，我们的目标是建立一个全面的促凋亡的bcl2信号网络 线粒体依赖的细胞死亡计划，这为治疗提供了共同点 干预措施。

Project Summary 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.