Molecular Regulation of Apoptosome Activity

描述(申请人提供)：细胞凋亡，或程序性细胞死亡，是多细胞生物体用来消除不需要的或受损的细胞以维持组织动态平衡的过程。它在发育、免疫反应和许多其他生理事件中起着关键作用。放松对细胞凋亡的调控可能会导致癌症、免疫紊乱和神经退行性疾病等疾病。从分子水平上讲，细胞凋亡是由caspase酶来实现的，而在哺乳动物中，caspase激活的主要途径是细胞色素c介导的途径。在这个途径中，caspase的激活是通过从线粒体释放细胞色素c和随后组装一个多聚体蛋白复合体来启动的，凋亡体是caspase的中心激活机制。最近，我们发现了一条控制凋亡体活性的新的调控途径。这一调控途径可由合成化合物α-(三氯甲基)-4-吡啶乙醇(PETcm)触发，并且该途径受肿瘤抑制因子PhaP(可能的人类白细胞抗原相关蛋白)和癌蛋白原胸腺素α(PROT)的调节，表明其可能参与肿瘤的发生。在这项研究中，我们将探讨PEMedici启动的凋亡体调控途径的分子机制，包括PEMedici启动该途径的机制，以及Phap刺激凋亡体活性的机制。此外，我们还将确定Phap的凋亡和抑瘤活性的结构基础，并测试Phap的凋亡活性是否有助于其抑瘤作用。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的技术。这项研究将有助于阐明死亡调控途径的分子机制，并有助于理解其生理功能。这项工作也应该有助于通过靶向这一途径来设计新的癌症疗法。

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.