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，以维持组织的动态平衡。它在发育、免疫等方面起着关键作用 反应和许多其他生理事件。放松对细胞凋亡的调控可能会导致疾病，如 癌症、免疫紊乱和神经退行性疾病。从分子上讲，细胞凋亡是通过 在哺乳动物中，caspase的主要激活途径是细胞色素。 C-介导途径。在这个途径中，caspase的激活是由细胞色素c的释放启动的。 线粒体和随后组装的多聚体蛋白复合体，即凋亡体，这是 中央caspase激活机制。最近，我们发现了一种新的调控途径，可以控制 凋亡体活性。这一调控途径可以由合成化合物触发， α-(三氯甲基)-4-吡啶乙醇(PETcm)，该途径受两种肿瘤的调节 抑制子Phap(可能的人类白细胞抗原相关蛋白)和癌蛋白胸腺素原-α(Prot)， 这表明它可能参与了肿瘤的发生。 在这项建议中，我们将研究PEMedici启动的凋亡体的分子机制。 -调节途径，包括PETCM启动该途径的机制，以及通过 其中Phap刺激凋亡体活动。此外，我们将确定 Phap的细胞凋亡和抑瘤活性，并检测Phap的凋亡活性 有助于它的肿瘤抑制作用。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。这项研究将阐明分子 死亡调控途径的机制，并有助于了解其生理功能。这 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。

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.