Molecular Regulation of Apoptosome Activity

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来维持组织内稳态。它在发育、免疫、 反应和许多其他生理事件。细胞凋亡的失调可导致疾病， 癌症、免疫紊乱和神经变性疾病。在分子上，细胞凋亡是由 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。在这一途径中，胱天蛋白酶的激活是由细胞色素c从 线粒体和随后的多聚体蛋白复合物的组装，即线粒体， 中央半胱天冬酶激活机制。最近，我们发现了一种新的调控途径， 异常活动。这种调节途径可以由合成化合物触发， α-（三氯甲基）-4-吡啶乙醇（PETCM），并且该途径受到肿瘤细胞和肿瘤细胞的调节。 抑制因子PHAP（推定的HLA相关蛋白）和癌蛋白原胸腺素-α（ProT）， 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， - 调节途径，包括PETCM启动该途径的机制，以及PETCM启动该途径的机制， 其中PHAP刺激线粒体活动。此外，我们将确定 PHAP的凋亡和抑瘤活性，并检测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，生物化学技术， 将使用分子生物学、细胞生物学和化学生物学。这项研究将阐明 死亡调节途径的机制，并促进其生理功能的理解。这 这项工作也应该有助于通过靶向这一途径设计新的癌症疗法。

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 researchwill 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.