Molecular Regulation of Apoptosome Activity

描述（由申请人提供）：细胞凋亡或程序性细胞死亡是多细胞生物体用于消除不需要的或受损的细胞以维持组织稳态的过程。它在发育，免疫反应和许多其他生理事件中起着关键作用。细胞凋亡的失调可导致疾病，如癌症、免疫紊乱和神经退行性疾病。在分子上，细胞凋亡是由称为半胱天冬酶的蛋白酶执行的，并且在哺乳动物中，主要的半胱天冬酶活化途径是细胞色素c介导的途径。在该途径中，胱天蛋白酶激活由细胞色素c从线粒体释放和随后的多聚体蛋白复合物的组装启动，所述多聚体蛋白复合物是中心胱天蛋白酶激活机制。最近，我们确定了一个新的调控途径，控制aptosome活动。这种调节途径可以由合成化合物α-（三氯甲基）-4-吡啶乙醇（PETCM）触发，并且该途径受到肿瘤抑制因子PHAP（推定的HLA相关蛋白）和癌蛋白原胸腺素-α（ProT）的调节，表明其可能参与肿瘤发生。在这个提议中，我们将研究PETCM启动的，溶酶体调节途径的分子机制，包括PETCM启动该途径的机制，以及PHAP刺激溶酶体活性的机制。此外，我们将确定PHAP的凋亡和肿瘤抑制活性的结构基础，并测试PHAP的凋亡活性是否有助于其肿瘤抑制特性。在进行这些研究时，将使用生物化学、分子生物学、细胞生物学和化学生物学技术。本研究将有助于阐明死亡调控通路的分子机制，并有助于理解其生理功能。这项工作也应该为通过靶向这一途径设计新的癌症疗法提供启示。

DESCRIPTION (provided by applicant): Apoptosis, or programmed cell death, is a process that multicellular organisms utilize to eliminate unwanted or damaged cells to maintain tissue homeostasis. It plays a critical role in development, immune responses and many other physiological events. Deregulation of apoptosis can lead to diseases such as cancer, immune disorders, and neurodegenerative diseases. Molecularly, apoptosis is executed by proteases known as caspases, and in mammals, a major caspase activation pathway is the cytochrome c-mediated pathway. In this pathway, caspase activation is initiated by cytochrome c release from mitochondria and subsequent assembly of a multimeric protein complex, the apoptosome, which is the central caspase activation machinery. Recently, we identified a new regulatory pathway that controls apoptosome activity. This regulatory pathway can be triggered by a synthetic compound, alpha-(trichloromethyl)-4-Pyridineethanol (PETCM), and the pathway is modulated by both the tumor suppressor PHAP (putative HLA-associated protein) and the oncoprotein prothymosin-alpha (ProT), indicating its potential involvement in oncogenesis. In this proposal, we will investigate the molecular mechanisms of the PETCM-initiated, apoptosome -regulatory pathway, including the mechanism by which PETCM initiates the pathway, and the mechanism by which PHAP stimulates apoptosome activity. In addition, we will determine the structural basis for the apoptotic and tumor suppressive activities of PHAP, and test whether the apoptotic activity of PHAP contributes to its tumor suppressive property. In conducting these studies, techniques of biochemistry, molecular biology, cell biology, and chemical biology will be used. This research will elucidate the molecular mechanisms of the death regulatory pathway and facilitate understanding of its physiological functions. This work should also shed light on designing novel cancer therapies by targeting this pathway.