MOLECULAR MECHANISMS OF PML MEDIATED GROWTH CONTROL

描述：(改编自研究人员的摘要)早幼粒细胞 白血病蛋白PML在生长控制、转化中的作用 抑制和细胞死亡，但其作用机制仍是谜。这些 其作用与蛋白质的亚细胞定位密切相关。在……里面 正常细胞，大多数PML形成核体，核体受 压力。PML核体是异质多蛋白复合体，是 在所有正常细胞类型的研究中发现，表明它们发挥着基本的作用 在哺乳动物细胞中。T(15；17)基因阻断急性早幼粒细胞白血病PML (APL)导致PML核体丢失。PML的后续中断 生长控制和细胞凋亡的作用被认为有助于 白血病的发生。PML在其他致病条件下被破坏，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，博登博士确定了核体 可能与生理相关的成分。这些组件包括 真核细胞翻译起始因子4E(EKF-4E)与富含Pro的 同源结构域蛋白PRH。此外，PRH和eIF-4E相互作用。她的数据表明 PML在调节选定的mRNAs的运输中起作用。此操作是 通过PML和eIF-4E之间的相互作用调节，具有 在RNA运输中已确定的功能。她已经证明了自行车的运输 D1mRNA被PML优先抑制，这可能是一种作用机制 PML的生长抑制活性。EIF-4E具有促有丝分裂和诱导致癌作用 转化表明该蛋白与PML在 细胞核可能与PML的生长控制功能有关。下列人士须入住公屋 髓系发育。因此，PRH-PML交互可以表示 生长控制和分化。她假设PML执行其 通过与其他蜂窝合作伙伴的关联来抑制生长， 例如eIF-4E和PRH，通过选择性地调节RNA运输。她建议： (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)决定PRH是否 调控PML及其生长抑制介导的RNA转运作用 作用，以及(3)用高分辨核磁共振研究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.