PROMYELOCYTIC LEUKEMIA PROTEINS ROLE IN APOPTOSIS

描述：(逐字改编自调查人员的摘要) 早幼粒细胞白血病蛋白PML被认为在生长控制中发挥作用， 转化抑制和细胞死亡，但其作用机制是 未知。这些功能与细胞的亚细胞定位密切相关。 蛋白质。在正常细胞中，大多数PML形成的核小体 当细胞承受压力时就会被破坏。一种染色体易位 干扰急性早幼粒细胞白血病(APL)患者的PML导致丢失 关于PML核物质。破坏PML的生长控制和凋亡作用 被认为与白血病的发生有关。大多数病毒都进化了 为了生存而绕过宿主细胞防御的机制，如细胞凋亡。 几种病毒在感染期间以PML身体为目标。调查员已经 研究单链RNA病毒对PML的影响，以更好地了解 它的生理功能。这种病毒，淋巴细胞性脉络膜脑膜炎病毒 (LCMV)，能够在组织培养中建立慢性感染：因此 必须破坏宿主细胞介导的细胞凋亡。这建立了一个系统，用于 PML及其在细胞凋亡中作用的研究。一种单一的病毒蛋白Z可以 将PML核体移位至细胞质。这种移位可能会导致 血清降低感染细胞经历细胞死亡的倾向 被剥夺了权利。调查人员发现了PML的一种以前未知的成分 核小体，核糖体蛋白PO。这种蛋白质在核中起着重要的作用 DNA修复、内切酶活性和细胞质在翻译中的作用。姿势 在结肠息肉和肿瘤中表达上调，提示其与 胞核中的PML可能与PML的凋亡作用有关。调查员 参与研究了PML函数的几个新方面，特别是 与Z、PO和一种新的富含Pro的同源结构域蛋白PRH和PRH的相互作用 PML在翻译中的作用。调查员假设PML 通过与其他细胞联合执行其促细胞凋亡的行动 合作伙伴和LCMV蛋白阻止这种活动。因为这个协会 对于含有PO等核糖体蛋白的PML，他们预测PML参与了 翻译控制，这一作用与其促细胞凋亡有关 功能。他们建议：(1)确定PML的其他细胞合作伙伴和 评估这些新伙伴是否会影响PML的凋亡作用；(2) 用高分辨核磁共振方法研究PML/Z相互作用 阐明这一脯氨酸相互作用基序基础；(3)确定 PML可能通过与PO的交互参与翻译控制 以及这一作用是否与PML的凋亡作用有关。澄清 PML的分子作用机制对肿瘤的治疗具有重要意义 了解急性早幼粒细胞白血病和某些病毒感染的进展。

DESCRIPTION: (adapted verbatim from the investigator's abstract) The promyelocytic leukemia protein PML has been ascribed roles in growth control, transformation suppression and cell death but its mechanism of action is unknown. These functions are closely tied to the subcellular localization of the protein. In normal cells, the majority of PML forms nuclear bodies which are disrupted when the cell undergoes stress. A chromosomal translocation disrupts PML in acute promyelocytic leukemia (APL) patients resulting in loss of PML nuclear bodies. Disruption of PML's growth control and apoptotic action is thought to contribute to leukemogenesis. Most viruses have evolved mechanisms to bypass host cell defenses such as apoptosis in order to survive. Several viruses target PML bodies during infection. The investigator has studied the effect of a single stranded RNA virus on PML to better understand its physiological function. This virus, lymphocytic choriomeningitis virus (LCMV), is able to establish chronic infection in tissue culture: thus, LCMV must disrupt host cell mediates apoptosis. This establishes a system for the study of PML and its role in apoptosis. A single viral protein, Z, can translocate PML nuclear bodies to the cytoplasm. This translocation may cause the decreased propensity of infected cells to undergo cell death when serum deprived. The investigator has identified a previously unknown component of PML nuclear bodies, the ribosomal protein PO. This protein has a nuclear role in DNA repair, endonuclease activities and a cytoplasmic role in translation. PO is upregulated in colon polyps and tumors suggesting that its association with PML in the nucleus may be related to PML's apoptotic action. The investigator are involved in studying several novel aspects of PML function, in particular interactions with Z, PO and a novel proline rich homeodomain protein PRH and the function of PML in translation. The investigator hypothesizes that PML executes its pro-apoptotic actions through association with other cellular partners and that LCMV proteins block this activity. Because of the association with PML with ribosomal proteins like PO, they predict that PML is involved in translational control and that this action is linked to its pro-apoptotic function. They propose to: (1) determine other cellular partners of PML and assess whether these new partners affect PML's apoptotic action; (2) investigate the PML/Z interaction using high resolution NMR methods to elucidate that basis of this proline interaction motif; (3) determine whether PML is involved in translational control perhaps through interaction with PO and whether this action could be linked to PML's apoptotic action. Elucidating the molecular mechanism of action of PML has important implications for understanding the progression of APL and certain viral infections.