Apoptotic Network Integrated at the Mitochondrion

描述（由申请人提供）：适当执行细胞死亡确保正常的生物过程，其失调导致人类疾病，从癌症到神经退行性疾病。细胞凋亡是一种受调控的细胞死亡形式。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。因此，进一步阐明凋亡信号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家族蛋白在线粒体调控细胞死亡与生存的决定，可分为三个亚家族：(1)多结构域抗凋亡的BCL-2、BCL-XL和MCL-1；(2)多结构域促凋亡BAX和BAK；(3)促凋亡的BH3-only分子（BH3s）。BH3s传递上游凋亡信号，通过激活BAX/BAK或灭活BCL-2/BCL-XL/MCL-1来促进细胞凋亡。基因功能缺失研究揭示了上游“激活因子”BH3s和下游BAX/BAK在激活线粒体依赖性细胞凋亡中的重要轴。作为对凋亡信号的响应，“激活剂”bh3，包括BID、BIM和PUMA，触发BAX和BAK的同质寡聚，使线粒体通透，导致细胞色素c外排到细胞质中，激活caspase。我们最近发现了BH3s激活BAX/BAK依赖的线粒体通透性的新机制。我们建议阐明这一新机制，并根据bh3启动细胞死亡的机制对其进行重新分类。BH3s激活BAX/BAK不仅可以触发apaf -1介导的caspase激活，还可以启动caspase不依赖的细胞死亡。对这种新型细胞死亡形式的进一步表征，为未来开发针对caspase激活缺陷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，以差异地调节caspase依赖性和非依赖性细胞死亡程序。总的来说，我们的目标是在激活线粒体依赖性细胞死亡程序中建立一个全面的促凋亡BCl-2信号网络，为治疗干预提供共同的基础。

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.