MOLECULAR MECHANISMS OF PML MEDIATED GROWTH CONTROL

描述：（改编自研究者摘要） 白血病蛋白PML被认为在生长控制、转化、分化和凋亡中起作用， 抑制和细胞死亡，但其作用机制仍然是谜。这些 作用与蛋白质的亚细胞定位密切相关。在 在正常细胞中，大多数PML形成核体，其由 应力PML核体是异质性多蛋白复合物， 在所有正常细胞类型的研究中发现， 在哺乳动物细胞中。t（15;17）干扰急性早幼粒细胞白血病的PML (APL)导致PML核小体的丢失。PML的后续中断 生长控制和凋亡作用被认为有助于 白血病发生PML在其他致病性疾病中被破坏，例如 脊髓小脑性共济失调，以及包括乳头状瘤和疱疹在内的几种病毒。 为了确定PML的分子功能，Borden博士鉴定了核小体 可能具有生理相关性的成分。这些组件包括 真核生物翻译起始因子（4 E，eKF-4 E）和富含脯氨酸的 同源域蛋白PRH。此外，PRH和eIF-4 E相互作用。她的数据显示 PML在特定mRNA转运的调节中起作用。这一行动是 通过PML和eIF-4 E之间的相互作用进行调节，eIF-4 E是一种具有 在RNA运输中的功能。她已经证明细胞周期蛋白的转运 PML优先抑制D1 mRNA，这可能是一种机制， PML的生长抑制活性。EIF-4 E是促有丝分裂的，并诱导致癌 转化表明这种蛋白质与PML的相关性， 细胞核可能与PML的生长调控功能有关。需要租住公屋， 骨髓发育因此，PRH-PML相互作用可能代表PRH-PML之间的联系。 生长控制和分化。她假设PML执行其 通过与其他细胞伴侣的结合抑制生长， 例如eIF-4 E和PRH，通过选择性调节RNA转运。她提议： (1)研究PML的RNA转运活性，并确定这是否 功能与其生长抑制作用有关，（2）确定PRH 调节PML介导的RNA转运作用和PML的生长抑制 作用，以及（3）使用高分辨率NMR研究PML/PRH相互作用 方法来阐明这种相互作用的基础。

DESCRIPTION: (Adapted from the investigator's abstract) The promyelocytic leukemia protein PML is ascribed roles in growth control, transformation suppression and cell death but its mechanism of action remains enigmatic. These actions are closely tied to the subcellular localization of the protein. In normal cells, the majority of PML forms nuclear bodies, which are modulated by stress. PML nuclear bodies are heterogeneous multiprotein complexes that are found in all normal cell types studies suggesting that they play a basic role in mammalian cells. The t(15;17) disrupts PML in acute promyelocytic leukemia (APL) resulting in loss of PML nuclear bodies. Subsequent disruptions of PML's growth control and apoptotic action are thought to contribute to leukemogenesis. PML is disrupted in other pathogenic conditions such as spinocerebellar ataxia, and by several viruses including papilloma and Herpes. To determine a molecular function for PML, Dr. Borden identified nuclear body components likely to be of physiological relevance. These components include eukaryotic translation initiation factor (4E (eKF-4E) and the proline-rich homeodomain protein PRH. In addition, PRH and eIF-4E interact. Her data suggest that PML acts in the regulation of transport of selected mRNAs. This action is modulated through an interaction between PML and eIF-4E, a protein with established functions in RNA transport. She has shown that transport of cyclin D1 mRNA is preferentially suppressed by PML presenting a possible mechanism for PML's growth suppression activity. EIF-4E is mitrogenic and induces oncogenic transformation suggesting that association of this protein with PML in the nucleus may be related to PML's growth control functions. PRH is required for myeloid development. Thus, the PRH-PML interaction may represent a link between growth control and differentiation. She hypothesizes that PML executes its growth suppression actions through association with other cellular partners, e.g. eIF-4E and PRH, by regulating RNA transport selectively. She proposes to: (1) Investigate the RNA transport activities of PML, and ascertain whether this function is related to its growth suppression action, (2) Determine whether PRH modulates RNA transport actions mediated by PML and PML's growth suppression action, and (3) Investigate the PML/PRH interaction using high-resolution NMR method to elucidate the basis of this interaction.