PROMYELOCYTIC LEUKEMIA PROTEINS ROLE IN APOPTOSIS

描述：（逐字改编自研究者摘要） 早幼粒细胞白血病蛋白PML被认为在生长控制中起作用， 转化抑制和细胞死亡，但其作用机制是 未知这些功能是密切相关的亚细胞定位的 蛋白质。在正常细胞中，大多数PML形成核体， 当细胞受到压力时会被破坏。染色体易位 破坏急性早幼粒细胞白血病（APL）患者的PML， PML核小体。破坏PML的生长控制和凋亡作用 被认为是导致白血病的原因大多数病毒都进化了 为了生存，绕过宿主细胞防御如凋亡的机制。 几种病毒在感染过程中靶向PML小体。研究者已 研究了单链RNA病毒对PML的影响， 其生理功能。这种病毒，淋巴细胞性脉络丛脑膜炎病毒 （LCMV），能够在组织培养中建立慢性感染：因此，LCMV 必须破坏宿主细胞介导的凋亡。这就建立了一个系统， PML及其在细胞凋亡中作用研究一个单一的病毒蛋白Z， 将PML核小体转移到细胞质中。这种易位可能会导致 受感染细胞在血清作用下经历细胞死亡的倾向降低， 一无所有研究者发现了一种以前未知的PML成分 核小体，核糖体蛋白PO。这种蛋白质具有核作用， DNA修复，核酸内切酶活性和翻译中的细胞质作用。PO 在结肠息肉和肿瘤中上调，表明其与 核内的PML可能与PML的凋亡作用有关。研究者 参与研究PML功能的几个新方面，特别是 与Z、PO和新的富含脯氨酸的同源结构域蛋白PRH的相互作用， PML在翻译中的作用。研究者假设PML 通过与其他细胞因子的结合， LCMV蛋白阻断了这种活性。由于协会 与PML的核糖体蛋白，如PO，他们预测，PML参与 翻译控制，这种作用与其促凋亡有关。 功能他们提出：（1）确定PML的其他细胞伙伴， 评估这些新伴侣是否影响PML的凋亡作用;（2） 使用高分辨率NMR方法研究PML/Z相互作用， 阐明这种脯氨酸相互作用基序基础;（3）确定是否 PML可能通过与PO相互作用参与翻译控制 以及这种作用是否与PML的凋亡作用有关。阐明 PML作用的分子机制对以下方面具有重要意义： 了解APL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.