Apoptotic Network Integrated at the Mitochondrion

描述（由申请人提供）：细胞死亡的正确执行确保了正常的生物过程，其失调导致人类疾病，从癌症到神经退行性疾病。细胞凋亡是细胞死亡的一种调节形式。细胞凋亡的损伤不仅是癌症发展的核心，而且使肿瘤对细胞毒性疗法难以治疗。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家族蛋白在线粒体处控制细胞死亡与存活的决定，并且可以分为三个亚家族：（1）多结构域抗凋亡BCL-2、BCL-XL和MCL-1;（2）多结构域促凋亡BAX和巴克;和（3）促凋亡仅BH 3分子（BH 3）。BH 3通过激活BAX/巴克或失活BCL-2/BCL-XL/MCL-1传递上游凋亡信号以促进凋亡。遗传功能丧失研究揭示了上游“激活剂”BH 3 s和下游BAX/巴克在激活依赖于细胞凋亡的细胞中的重要轴。响应于细胞凋亡信号，“激活剂”BH 3，包括BID、BIM和BAKA，触发BAX和BAK的同源寡聚化以透化线粒体，导致细胞色素c流出到细胞溶质以激活半胱天冬酶。我们最近发现了一种新的机制，通过这种机制，BH 3激活BAX/巴克依赖的线粒体透化。我们建议阐明这种新的机制，并重新分类BH 3的基础上，他们在启动细胞死亡的机制。BH 3s激活BAX/巴克不仅触发APAF-1介导的caspase激活，而且启动caspase非依赖性细胞死亡。对这种新型细胞死亡形式的进一步表征为靶向具有缺陷性半胱天冬酶激活的癌细胞的抗癌疗法的未来发展提供了希望。我们还在研究BAX和巴克是否存在于不同的蛋白复合物中，以差异调节半胱天冬酶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，激活依赖于细胞死亡程序，这为治疗干预提供了共同基础。

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.